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WO2016154051A1 - Combination therapy for treating infections diseases - Google Patents

Combination therapy for treating infections diseases Download PDF

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Publication number
WO2016154051A1
WO2016154051A1 PCT/US2016/023256 US2016023256W WO2016154051A1 WO 2016154051 A1 WO2016154051 A1 WO 2016154051A1 US 2016023256 W US2016023256 W US 2016023256W WO 2016154051 A1 WO2016154051 A1 WO 2016154051A1
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WIPO (PCT)
Prior art keywords
optionally substituted
pharmaceutical composition
certain embodiments
alkyl
compound
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PCT/US2016/023256
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French (fr)
Inventor
Robert William HUIGENS, III
Yasmeen ABOUELHASSAN
Aaron GARRISON
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University of Florida
University of Florida Research Foundation Inc
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University of Florida
University of Florida Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Infectious diseases are the third leading cause of death in developed countries and the second leading cause of death worldwide (see, e.g., World Health Organization (WHO) Geneva, World Health Report (2002); Nathan, Nature (2004) 431 :899).
  • the efficacy of many antibacterial drugs has been compromised by the emergence of drug resistant, pathogenic bacteria (see, e.g., National Nosocomial Infections Surveillance (NNIS) System, Am. J. Infect. Control (2004) 32:470).
  • NIS National Nosocomial Infections Surveillance
  • the Infectious Disease Society of America has recently outlined the deadly implications of a growing number of drug-resistant pathogens (see, e.g., Boucher et ah, J. Clin. Infect. Dis. (2009) 48: 1).
  • Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and penicillin-resistant Streptococcus epidermis are especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis is especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis are especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis penicillin-resistant Streptococcus epidermis
  • Biofilms are complex communities of microorganisms that are commonly found on a variety of substrates or surfaces that are moist or submerged (Musk et ah, Curr. Med. Chem., 2006, 13, 2163). Though primarily populated by bacteria, biofilms can also contain many different individual types of microorganisms, e.g., bacteria, archaea, protozoa, and algae. The formation of biofilms can be thought of as a developmental process in which a few free-swimming (planktonic) bacteria adhere to a solid surface and, in response to appropriate signals, initiate the formation of a complex sessile microcolony existing as a community of bacteria and other organisms.
  • planktonic planktonic
  • Bacteria within biofilms are usually embedded within a matrix, which can consist of protein, polysaccharide, nucleic acids, or combinations of these macromolecules.
  • the matrix is a critical feature of the biofilm that protects the inhabiting organisms from antiseptics, microbicides, and host cells. It has been estimated that bacteria within biofilms are upwards of 1,000-fold more resistant to conventional antibiotics (Rasmussen et al., Int. J. Med. Microbiol., 2006, 296, 149). Accordingly, there is a need for development of new therapies to treat infectious diseases such as bacterial infections and/or biofilm.
  • the large majority of the antibiotic arsenal hits relatively few bacterial targets (e.g., cell wall synthesis machinery, bacterial ribosomes, DNA gyrase/topoisomerase, RNA polymerase) (K. Lewis, Nat. Rev. Drug Discov. 2013, 12, 371- 387).
  • bacterial targets e.g., cell wall synthesis machinery, bacterial ribosomes, DNA gyrase/topoisomerase, RNA polymerase
  • the present invention provides compositions comprising a quinoline and a potentiating agent, wherein the potentiating agent comprises a catechol moiety.
  • the present invention provides compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiet and optionally a surfactant.
  • the provided composition can be used to incorporate into, coat, impregnate, flush, or rinse an object or material.
  • the composition is a cleaning composition.
  • the provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm ⁇ e.g., tubing).
  • the present invention provides pharmaceutical compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiety, and optionally a pharmaceutically acceptable excipient.
  • the quinoline is a halogenated quinoline (HQ), i.e., comprising at least one halogen substituent.
  • the quinoline comprises at least one -N0 2 substituent.
  • the quinoline is a halogenated quinoline comprising at least one -N0 2 substitutent.
  • the potentiating agent acts to promote the antibacterial "potentiation" of the quinoline.
  • the potentiating agent may lower the minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy.
  • the potentiating agent is a phytochemical.
  • phytochemicals refer to chemical compounds that occur naturally in plants or are derived from plants.
  • the potentiating agent is gallic acid, caffeic acid, or tiron.
  • the potentiating agent is gallic acid.
  • the pharmaceutical composition further comprises a second antimicrobial agent such as an antibiotic.
  • the pharmaceutical composition further comprises a salt.
  • the salt is a metal (II) salt.
  • the quinoline is of Formula (I):
  • the quinoline is of Formula (II):
  • the quinoline is of Formula (III):
  • the quinoline is of Formula (IV):
  • the quinoline is of Formula (V):
  • the present invention provides a compound of Formula (C-1)
  • the present invention provides methods to treat and/or prevent an infectious disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the infectious disease is a bacterial infection.
  • the bacterial infection is a chronic bacterial infection.
  • the bacterial infection is a urinary tract infection, gastritis, respiratory tract infection (e.g., those seen in patients with cystic fibrosis), cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, ear infection, and sinus infection.
  • the bacterial infection is a Gram-negative bacterial infection.
  • the Gram-negative bacterium is A. baumannii or K. pneumonia.
  • the bacterial infection is a Gram-positive bacterial infection.
  • the Gram-positive bacterium is S. aureus or S. epidermidis.
  • the bacterium is an antibiotic-resistant strain.
  • the bacterium is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE).
  • the bacterium is an antibiotic-susceptible strain.
  • the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, sulfonamides, aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides, oxazolidinones, ansamycins, quinolones, streptogramins, and lipopeptides.
  • the subject having or susceptible to the infectious disease also contracts another disease or condition.
  • the subject is diagnosed with cystic fibrosis.
  • the infectious disease is a fungal infection. In certain embodiments, the infectious disease is a parasital infection. In certain embodiments, the infectious disease is a protozoan infection. In certain embodiments, the infectious disease is associated with the formation of a biofilm.
  • the present invention provides methods for killing a bacterium comprising contacting the bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods for inhibiting bacterial cell growth comprising contacting the bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods for inducing bacterial hypersusceptibility comprising contacting a bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods of preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the present invention provides methods of eradicating a biofilm comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the biofilm includes one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae.
  • the biofilm includes bacteria.
  • the present invention provides methods of treating and/or preventing biofilm formation comprising contacting an object with an effective amount of the pharmaceutical composition as described herein.
  • the provided method is useful in inhibiting and/or removing a biofilm on the surface of an object.
  • the biofilm is produced by an organism selected from the group consisting of bacteria, archaea, algae, fungi, and protozoa.
  • the biofilm is a bacterial biofilm.
  • the biofilm includes antibiotic- resistant bacteria.
  • the biofilm includes MRSA.
  • the quinoline in the provided pharmaceutical compositions may bind metal ions and thereby provide their antibacterial properties.
  • the quinoline in the provided pharmaceutical compositions binds iron and/or other metals (e.g. , aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uranium)).
  • metals e.g. , aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uran
  • the quinoline in the provided pharmaceutical compositions binds metal(II) ions.
  • the metal (II) ion(s) is/are Zn 2+ , Fe 2+ , and/or Cu 2+ .
  • the quinoline in the provided pharmaceutical compositions chelates Fe and one or more metals important for bacterial growth, e.g. K, Mg, Ca, Mn, Zn, Co, Cu, and Mo.
  • the invention provides a kit for treating and/or preventing an infectious disease.
  • the invention provides a kit for preventing formation of biofilms.
  • the invention provides a kit for eradicating biofilms.
  • the kit is to treat and/or prevent biofilm formation in a subject.
  • the kit is to treat and/or prevent biofilm formation on an object (e.g. surface).
  • the kit further comprises an antimicrobial agent (e.g. , antibiotics).
  • the inventive kits include a first container containing a therapeutically effective amount of a pharmaceutical composition as described herein, and instructions for administering the pharmaceutical composition to the subject to treat and/or prevent an infectious disease.
  • kits include a first container containing an effective amount of a composition as described herein, and instructions for using the composition to prevent and/or eradicate a biofilm.
  • the kit is a cleaning kit.
  • the kit further comprises a disinfectant.
  • a kit may also include multiple unit dosages, for example, for multiple days of treatment.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates plane polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture.”
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched” or “enantiomerically enriched.” “Optically enriched” and
  • enantiomeric ally enriched means that a provided compound is made up of a significantly greater proportion of one enantiomer.
  • a compound of the present invention is made up of at least about 70% by weight of a preferred enantiomer.
  • a compound of the present invention is made up of at least about 80% by weight of a preferred enantiomer.
  • a compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer.
  • the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the depicted structures that differ only in the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by 13 C or 14 C are within the scope of this invention.
  • Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • CiV is intended to encompass, Ci, C 2 , C 3 , C 4 , C5, C 6 , Ci_6, Ci_5, Ci ⁇ , Ci_ 3 , Ci_ 2 , C 2 _6, C 2 _5, C 2 ⁇ , C 2 _ 3 , C 3 _6, C 3 _5, C 3 ⁇ , C4_6, C 4 _5, and Cs_6.
  • purified refers to a compound useful in the present invention being free of other, dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, 20%, 50%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% of the mass, by weight, of a given sample or composition. In one embodiment, these terms refer to the compound comprising at least 95%, 98%, 99%, or 99.9% of the mass, by weight, of a given sample or composition.
  • R XI is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R XI groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • aliphatic includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, and cyclic (i.e. , carbocyclic)
  • hydrocarbons which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes straight, branched and cyclic alkyl groups.
  • An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like.
  • alkyl encompass both substituted and unsubstituted groups.
  • aliphatic is used to indicate those aliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • Aliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroarylthioxy acyloxy, and the like, each of which may or may not be further substituted).
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • the alkyl group employed in the invention contains 1-20 carbon atoms.
  • the alkyl group employed contains 1-15 carbon atoms.
  • the alkyl group employed contains 1-10 carbon atoms.
  • the alkyl group employed contains 1-8 carbon atoms.
  • the alkyl group employed contains 1-5 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl (e.g.
  • Alkyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • alkenyl denotes a monovalent group derived from a straight- or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • the alkenyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkenyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkenyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkenyl group contains 2-8 carbon atoms. In yet other embodiments, the alkenyl group contains 2-5 carbons.
  • Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten- 1-yl, and the like, which may bear one or more substituents.
  • Alkenyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • alkenyl group e stereochemistry is not specified (e.g.,
  • alkynyl refers to a monovalent group derived from a straight- or branched-chain hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • the alkynyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkynyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkynyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkynyl group contains 2-8 carbon atoms. In still other embodiments, the alkynyl group contains 2-5 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl
  • Alkynyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroaliphaticoxy alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -
  • each instance of is, independently, selected from Cuo alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, Ce-i 4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered
  • heterocyclyl or 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, Ce-i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, Ce- ff
  • io aryl and 5-10 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, -OH, -OR aa , -ON(R bb ) 2 ,
  • each instance of is, independently, selected from CM O alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _ioalkenyl, heteroC 2 _ioalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa ,
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _io alkenyl, heteroC 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
  • heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • amino refers to a group of the formula (-NH 2 ).
  • a "substituted amino” refers either to a mono-substituted amine (-NHR h ) of a disubstituted amine (-NR h 2 ), wherein the R h substituent is any substituent as described herein that results in the formation of a stable moiety (e.g., a suitable amino protecting group; aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, amino, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
  • heteroarylamino alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • the R h substituents of the disubstituted amino group(-NR h 2 ) form a 5- to 6-membered heterocyclic ring.
  • alkoxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted alkyl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • alkylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted alkyl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • alkylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted alkyl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • aryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which all the ring atoms are carbon, and which may be substituted or unsubstituted.
  • aryl refers to a mono, bi, or tricyclic C 4 -C 2 o aromatic ring system having one, two, or three aromatic rings which include, but not limited to, phenyl, biphenyl, naphthyl, and the like, which may bear one or more substituents.
  • Aryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • arylalkyl refers to an aryl substituted alkyl group, wherein the terms “aryl” and “alkyl” are defined herein, and wherein the aryl group is attached to the alkyl group, which in turn is attached to the parent molecule.
  • exemplary arylalkyl groups are benzyl and phenethyl.
  • aryloxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted aryl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • arylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted aryl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • arylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted aryl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • halo and halogen refer to an atom selected from fluorine
  • heteroaliphatic refers to an aliphatic moiety, as defined herein, which includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, cyclic (i.e. , heterocyclic), or polycyclic hydrocarbons, which are optionally substituted with one or more functional groups, and that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more substituents.
  • heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic includes the terms
  • heteroalkyl “heteroalkenyl”, “heteroalkynyl”, and the like. Furthermore, the terms
  • heteroalkyl encompass both substituted and unsubstituted groups.
  • heteroaliphatic is used to indicate those heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • Heteroaliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroarylamino alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroalkyl refers to an alkyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkenyl refers to an alkenyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkynyl refers to an alkynyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkylamino refers to a "substituted amino" of the formula (-
  • R h is, independently, a hydrogen or an optionally substituted heteroalkyl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • heteroalkyloxy refers to a "substituted hydroxyl" of the formula (-
  • R 1 is an optionally substituted heteroalkyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • heteroalkylthioxy refers to a "substituted thiol" of the formula (-
  • R r is an optionally substituted heteroalkyl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _i 4 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3 _io carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _ 8 carbocyclyl”).
  • carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _7 carbocyclyl”).
  • carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, carbocyclyl group has 4 to 6 ring carbon atoms ("C4_6 carbocyclyl”). In some embodiments, carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”).
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the
  • C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _i 4 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _i 4 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _i 4 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl").
  • a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“Cs_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl”). Examples of Cs_6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C5).
  • C 3 _ 6 cycloalkyl groups include the aforementioned Cs_ 6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 _i 4 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3 _i 4 cycloalkyl.
  • heterocyclic refers to a cyclic heteroaliphatic group.
  • a heterocyclic group refers to a non-aromatic, partially unsaturated or fully saturated, 3- to 12-membered ring system, which includes single rings of 3 to 8 atoms in size, and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or heteroaryl groups fused to a non-aromatic ring.
  • These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • Heterocyclyl groups include, but are not limited to, a bi- or tri-cyclic group, comprising fused five, six, or seven- membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • heterocycles include azacyclopropanyl, azacyclobutanyl, 1,3-diazatidinyl, piperidinyl, piperazinyl, azocanyl, thiaranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, thiacyclohexanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, dioxanyl, oxathiolanyl, morpholinyl, thioxanyl, tetrahydronaphthyl, and the like, which may bear one or more substituents.
  • Substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroaryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • heteroaryls include, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, quinazolynyl, phthalazinyl, naphthridinyl,
  • Heteroaryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroarylamino refers to a "substituted amino' Of the (-NR h 2 ), wherein R h is, independently, hydrogen or an optionally substituted heteroaryl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • heteroaryloxy refers to a "substituted hydroxyl" of the formula (-
  • R 1 is an optionally substituted heteroaryl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • heteroarylthioxy refers to a "substituted thiol" of the formula (-
  • R r is an optionally substituted heteroaryl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • hydroxy or "hydroxyl” refers to a group of the formula (-OH).
  • substituted hydroxyl refers to a group of the formula (-OR 1 ), wherein R 1 can be any substituent which results in a stable moiety (e.g., a suitable hydroxyl protecting group;
  • nitro refers to a group of the formula (-N0 2 ).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • a "protecting group” is well known in the art and include those described in detail in Greene 's Protective Groups in Organic Synthesis, P. G. M. Wuts and T. W. Greene, 4 edition, Wiley-Interscience, 2006, the entirety of which is incorporated herein by reference.
  • Suitable “amino-protecting groups” include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo- 10,10, 10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,
  • TLBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)- l- methylethyl carbamate (i-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, i-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, i
  • tungsten)carbonyl] amine N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzene
  • the substituent present on an oxygen atom is an hydroxyl protecting group.
  • a "hydroxyl protecting group” (also referred to as an “oxygen protecting group”) is well known in the art and includes those described in detail in Greene (1999).
  • Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), /?-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), i-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-
  • DEIPS diethylisopropylsilyl
  • TDMS i-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-/?-xylylsilyl, triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,
  • protecting groups include methylene acetal, ethylidene acetal, 1-i-butylethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide,
  • cyclopentylidene ketal cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p- methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, ⁇ - ⁇ N,N- dimethylamino)ethylidene derivative, a-(N,N'-dimethylamino)benzylidene derivative, 2- oxacyclopentylidene ortho ester, di
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions ⁇ e.g. , F , CF, Br , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HC0 3 ⁇ HS0 4 , sulfonate ions (e.g.
  • exemplary counterions which may be multivalent include C0 3 , HP0 4 ,
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the
  • carbohydrate refers to an aldehydic or ketonic derivative of polyhydric alcohols.
  • Carbohydrates include compounds with relatively small molecules (e.g. , sugars) as well as macromolecular or polymeric substances (e.g. , starch, glycogen, and cellulose polysaccharides).
  • saccharide refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates.
  • monosaccharides can be represented by the general formula C y H 2y O y (e.g., C 6 Hi 2 0 6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3.
  • C y H 2y O y e.g., C 6 Hi 2 0 6 (a hexose such as glucose)
  • y is an integer equal to or greater than 3.
  • Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides.
  • deoxyribose is of the formula CsHio0 4 and is a monosaccharide.
  • Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively.
  • the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose.
  • Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively.
  • Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively.
  • aldotetrose sugars include erythrose and threose
  • ketotetrose sugars include erythrulose.
  • Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose.
  • aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose.
  • Ketoheptose sugars include sedoheptulose.
  • the aldohexose D-glucose for example, has the formula C 6 Hi206, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e. , 2 4 ) possible stereoisomers.
  • the assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar.
  • the aldehyde or ketone group of a straight- chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
  • the carbon atom containing the carbonyl oxygen becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring.
  • the resulting possible pair of stereoisomers is called anomers.
  • an a anomer the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the - CH 2 OH side branch.
  • the alternative form, in which the -C3 ⁇ 4OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a ⁇ anomer.
  • a carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g. , a trisaccharide), respectively.
  • Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, and rutinose.
  • Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose.
  • carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate
  • basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.
  • Basic addition salts refer to salts derived from appropriate bases, these salts including alkali metal, alkaline earth metal, and quaternary amine salts. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds, often by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium (by using, e.g. , NaOH), potassium (by using, e.g.
  • KOH potassium hydroxide
  • calcium by using, e.g. , Ca(OH) 2
  • magnesium by using, e.g. , Mg(OH) 2 and magnesium acetate
  • zinc by using, e.g. , Zn(OH) 2 and zinc acetate
  • aluminum as well as nontoxic quaternary amine cations such as ammonium
  • tetramethylammonium tetraethylammonium
  • methylamine dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N-dibenzylethylenediamine.
  • organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone, imidazole, n-methyl-d-glucamine, ⁇ , ⁇ '- dibenzylethylenediamine, N,A ⁇ -diethylethanolamine, N,A ⁇ -dimethylethanolamine, triethanolamine, and tromethamine.
  • Basic amino acids e.g. , 1-glycine and 1-arginine
  • amino acids which may be zwitterionic at neutral pH e.g. , betaine (N,N,N-trimethylglycine) are also contemplated.
  • tautomer refers to a particular isomer of a compound in which a hydrogen and double bond have changed position with respect to the other atoms of the molecule. For a pair of tautomers to exist there must be a mechanism for interconversion. Examples of tautomers include keto-enol forms, imine-enamine forms, amide-imino alcohol forms, amidine-aminidine forms, nitroso-oxime forms, thio ketone-enethiol forms, N-nitroso- hydroxyazo forms, nitro-acz-nitro forms, lactam-lactim forms, ketene-ynol forms, enamine- enamine forms, and pyridione-hydroxypyridine forms.
  • polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of the invention may be prepared, e.g. , in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • a hydrate of a compound may be represented, for example, by the general formula R xH 2 0, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g. , monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g. , hemihydrates (R 0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g. , dihydrates (R-2H 2 0) and hexahydrates (R-6H 2 0)).
  • the term "subject" refers to any animal.
  • the subject is a mammal.
  • the subject is a human (e.g., a man, a woman, or a child).
  • the human may be of either sex and may be at any stage of development.
  • the subject has been diagnosed with the condition or disease to be treated.
  • the subject is at risk of developing the condition or disease.
  • the subject is an experimental animal (e.g. , mouse, rat, rabbit, dog, pig, or primate).
  • the experimental animal may be genetically engineered.
  • the subject is a domesticated animal (e.g. , dog, cat, bird, horse, cow, goat, sheep).
  • administer refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition condition
  • disease and “disorder” are used interchangeably.
  • an "effective amount" of a compound of the present invention or a pharmaceutical composition thereof refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • an effective amount is a cleaning-effective amount.
  • the "cleaning-effective" amount of the compound refers to an amount of the compound as described herein which is necessary to remove at least 10% of bacteria from a biofilm as determined by a reduction in numbers of bacteria within the biofilm when compared with a biofilm not exposed to the compound.
  • the effective amount is a prophylactically effective amount to prevent normal biofilm formation between normal cleaning times as determined by a statistically significant increase in the number of cells within a biofilm or upon a clean surface. Prevention of normal biofilm formation is determined by the ability to disperse a biofilm using surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm.
  • the treated biofilm must be shown to release 10% or more of its bacteria when compared with a similar biofilm that is not treated when both biofilms are exposed to surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm.
  • a "therapeutically effective amount" of a compound of the present invention or a pharmaceutical composition thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, e.g., iron overload, or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for chelating a metal described herein.
  • a therapeutically effective amount is an amount sufficient for treating a pathological condition described herein. In certain embodiments, a therapeutically effective amount is an amount sufficient for chelating a metal described herein and for treating a pathological condition described herein.
  • a prophylactically effective amount of a compound of the present invention is an amount sufficient to prevent a condition, e.g. , iron overload, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for chelating a metal described herein.
  • a prophylactically effective amount is an amount sufficient for preventing a pathological condition described herein. In certain embodiments, a prophylactically effective amount is an amount sufficient for chelating a metal described herein and for preventing a pathological condition described herein.
  • tissue sample refers to any sample including tissue samples
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • “Chelation,” “chelating,” “sequestration,” or “sequestering” is the formation or presence of two or more separate coordinate bonds between a polydentate (multiple- bonded) compound and a single central atom.
  • the polydentate compound is typically an organic compound and referred to as a "chelator,” “chelant,” “chelating agent,”
  • the central atom is usually a metal atom or metal ion (e.g., a metal atom or metal ion described herein, such as iron (e.g., Fe(II)), Zn(II), and Cu (II), etc.).
  • the chelator may form a stable complex with the central atom through coordinate bonds, inactivating the central atom so that the central atom is less likely to react with other molecules or atoms.
  • antimicrobial refers to a compound or composition having a destructive killing action upon microbes or microorganisms.
  • microorganism refer to very minute, microscopic life forms or organisms, which may be either plant or animal, and which may include, but are not limited to, algae, bacteria, fungi, protozoae, and parasites.
  • biofilm formation refers to the attachment of microorganisms to surfaces and the subsequent development of multiple layers of cells.
  • the biofilm is bacterial biofilm.
  • fungicide refers to a compound or composition having either a fungicidal or fungistatic effect upon fungi contacted by the compound or comosition.
  • Figure 1 shows exemplary quinoline compounds useful in the present invention.
  • Figures 2 A to 2B show ( Figure 2A) Friedlander quinoline synthesis used to synthesize quinolines 8-11; and ( Figure 2B) structures of exemplified potentiating agents.
  • Figures 3A to 3D show ( Figure 3A) antibacterial potentiation of quinolin compounds 1, 21 and 22 with GA against S. aureus 29213; ( Figure 3B) biofilm eradication potentiation of quinoline compound 1 with Gallic Acid against MRSA-2; ( Figure 3C) Metal(II) cation potentiation with 5 against S. aureus 29213; and ( Figure 3D) kill curves for quinoline compound 1 and GA as single agents and in combination against S. aureus 29213.
  • Figure 4 shows a potentiation of antibacterial activity assay (determined by
  • Figure 5 shows kill kinetics for quinoline 1 against S. aureus 29213 to make final concentrations of 2x, 4x, and 16x MIC for quinoline 1.
  • Figure 6 shows kill kinetics for halogenated quinoline 1 against S. aureus
  • Figure 7 shows cytotoxicity results of exemplary quinoline compounds
  • S.I. selectivity index; IC50/MIC values to show antibacterial selectivity.
  • Figure 9 shows exemplary quinoline potentiation with gallic acid (GA) against methicillin-resistant S. aureus clinical isolates.
  • Figure 11 shows metal(II) cation (100 ⁇ ) potentiation studies with quinolines against Staphylococcus aureus ATCC 29213.
  • * partial reduction in turbidity at highest test concentrations.
  • Figure 12 shows gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 13 shows additional gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 14 shows caffeic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 15 shows tiron potentiation of antibacterial activity against S. aureus
  • Figure 16 shows gallic acid potentiation of antibacterial activity against
  • Figure 17 shows gallic acid potentiation of antibacterial activity against
  • Figure 18 shows gallic acid potentiation of antibacterial activity against S. aureus BAA-1707 and gallic acid potentiation of antibacterial activity against SA-156 (MRS A).
  • Figure 19 shows gallic acid potentiation of antibacterial activity against S. epidermidis ATCC 12228 and gallic acid potentiation of antibacterial activity against S. epidermidis MRSE-1.
  • Figure 20 shows gallic acid potentiation of antibacterial activity against
  • Figure 21 shows gallic acid potentiation of antibacterial activity against
  • PAOl Pseudomonas aeruginosa
  • Figure 22 shows ZnCl 2 -mediated potentiation of antibacterial activity against
  • Figure 23 shows (NH 4 )Fe(S0 4 ) 2 -mediated potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 24 shows CuS0 4 -mediated potentiation of antibacterial activity against
  • Figure 25A shows evaluation of exemplary quinoline compounds in MRSA-2 biofilm dispersion assay
  • Figure 25B shows evaluation of exemplary quinoline compounds in S. epidermidis biofilm dispersion assay
  • Figure 25C shows dose-response curve for compound A2 against MRSA-2 biofilm.
  • Infectious diseases are caused by microbes such as bacteria, fungi, and parasites. These pathogenic micobes typically require one or more metals (e.g., iron, calcium, magnesium, strontium, potassium, sodium, chromium, copper, manganese, molybdenum, zinc, and tungsten) to sustain life.
  • metals e.g., iron, calcium, magnesium, strontium, potassium, sodium, chromium, copper, manganese, molybdenum, zinc, and tungsten
  • inventive pharmaceutical compositions comprising a quinoline compound, a potentiating agent, and optionally a pharmaceutically acceptable excipient, can be used in the treatment and/or prevention infectious diseases.
  • compositions may act as metal chelators to interrupt the bacterial growth. Further provided herein are methods of using the provided pharmaceutical compositions to prevent or treat infectious disease. Also provided herein are methods of using the provided pharmaceutical compositions to prevent or eradicate biofilms. Compositions and Kits
  • the invention also provides a composition comprising a quinoline and a potentiating agent.
  • the invention provides a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient.
  • the quinoline is a
  • halogenated quinoline i.e. comprising at least one halogen substituent.
  • the quinoline comprises at least one N0 2 substituent.
  • the quinoline is a halogenated quinoline comprising at least one N0 2 substitutent.
  • the quinoline is a compound of any one of Formulae (I)-(V) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.
  • compositions comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a compound of Formula (C-I), or a pharmaceutically acceptable salt thereof).
  • the potentiating agent acts to promote the antibacterial "potentiation" of the quinoline.
  • the potentiating agent may lower minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy.
  • the potentiating agent is a phytochemical.
  • phytochemicals refer to chemical compounds that occur naturally in plants.
  • exemplary phytochemicals include, but are not limited to, alkaloids (e.g. caffeine, theobromine, or theophylline), anthocyanins (e.g. cyanidin or malvidin), carotenoids (e.g. beta-carotene, lutein, or lycopene), coumestans, flavan-3-ols, flavonoids (e.g.
  • hydroxytyrosol monoterpenes (e.g. geraniol, limonene, organosulfides, allicin, glutathione, indole-3-carbinol, isothiocyanates, or sulforaphane), damnacanthal, digoxin, phytic acid, phenolic acids (e.g. capsaicin, ellagic acid, gallic acid, rosmarinic acid, tannic acid), phytosterols, beta-sitosterol, saponins, stylbenes (e.g. pterostilbene, resveratrol),
  • monoterpenes e.g. geraniol, limonene, organosulfides, allicin, glutathione, indole-3-carbinol, isothiocyanates, or sulforaphane
  • damnacanthal digoxin
  • phytic acid phenolic acids (e.g. capsa
  • triterpenoids triterpenoids, ursolic acid, xanthophylls, astaxanthin, and beta-cryptoxanthin.
  • the potentiating agent comprises a catechol moiety.
  • a catechol moiety refers to an optionally substituted, 1,2-dihydroxybenzyl moiety of the formula: . it is understood that the catechol moiety also encompass derivatives of 1,2-dihydroxybenzyl.
  • the derivatives of 1,2-dihydroxybenzyl can include additional substituents on the phenyl ring and/or protecting groups on one or two of the hydroxyl groups.
  • R A , R B , and R C" are as defined herein.
  • the potentiating agent is gallic acid, caffeic acid, or tiron. In certain embodiments, the potentiating agent is gallic acid.
  • the potentiating agent is present at about 1/100 of its
  • the potentiating agent is present at about 1/60 of its MIC. In certain embodiments, the potentiating agent is at about 1/30 of its MIC. In certain
  • the potentiating agent is at about 1/20 of its MIC. In certain embodiments, the potentiating agent is at about 1/10 of its MIC. In certain embodiments, the potentiating agent is at about 1/8 of its MIC. In certain embodiments, the potentiating agent is at about 1/7 of its MIC. In certain embodiments, the potentiating agent is at about 1/6 of its MIC. In certain embodiments, the potentiating agent is at about 1/5 of its MIC. In certain embodiments, the potentiating agent is at about 1/4 of its MIC. In certain embodiments, the potentiating agent is at about 1/3 of its MIC. In certain embodiments, the potentiating agent is at about 1/2 of its MIC. In certain embodiments, the potentiating agent is at about 1/1 of its MIC.
  • the molar ratio of the quinoline to the potentiating agent is about 10 10 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 6 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 5 :1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 4 : 1 to about 1: 1.
  • the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 100: 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10: 1 to about 1 : 1.
  • the quinoline is provided in an effective amount in the composition.
  • the combination of quinoline and the potentiating agent is provided in an effective amount in the composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactic ally effective amount.
  • the effective amount is a clean-effective amount.
  • the effective amount is to prevent biofilm formation.
  • the effective amount is to eradicate or remove biofilm formed.
  • the provided composition further comprises a surfactant.
  • the surfactant is selected from the group consisting of anionic, nonionic, amphoteric, biological surfactants, and mixtures thereof.
  • the provided composition further comprises one or more disinfecting agents.
  • Disinfecting agents can comprise alcohols (such as ethanol or isopropanol), aldehydes (such as glutaraldehyde), oxidizing agents (such as sodium hypochlorite, calcium hypochlorite, chloramine, hydrogen peroxide, iodine, peracetic acid, performic acid, potassium
  • a disinfectant can be a spray or a liquid.
  • a disinfectant can be concentrated or ready-to-use.
  • a disinfectant can be for commercial or household use.
  • a composition of the invention can also be incorporated into household disinfectants, laundry detergent, and household cleaning solutions.
  • the provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm (e.g. tubing). Therefore, in some embodiments, a method of the invention includes rinsing or decontaminating a surface by contacting the surface with a composition of the invention. Further, in some embodiments, a method of the invention includes inhibiting biofilm growth or preventing biofilm growth by incorporating, coating, impregnating, flusing, or rinsing an object with the provided composition. In some embodiments, a composition of the invention can be incorporated into a surface by coating or impregnating the surface of an object. [00127] In certain embodiments, the uinoline is of Formula (I):
  • each instance of R A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur;
  • each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; each instance of R is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
  • R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
  • R 1 is hydrogen. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is F. In certain embodiments, R 1 is CI. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is N0 2 . In certain embodiments, R 1 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 1 is substituted C 1-6 alkyl. In certain embodiments, R 1 is optionally substituted carbocyclyl. In certain embodiments, R 1 is optionally substituted cyclohexyl. In certain embodiments, R 1 is optionally substituted aryl. In certain
  • R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is F. In certain embodiments, R 2 is CI. In certain embodiments, R 2 is Br. In certain embodiments, R 2 is I. In certain embodiments, R 2 is N0 2 . In certain embodiments, R 2 is optionally substituted alkyl. In certain embodiments, R is optionally substituted C 1-6 alkyl. In certain embodiments,
  • R 2 is unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 2 is substituted Ci_ 6 alkyl. In certain embodiments, R 2 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
  • R 2 is optionally substituted phenyl. In certain embodiments, R 2 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 2 is optionally substituted furanyl. In certain embodiments, R 2 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 2 is -OR A , wherein R A is as defined herein. In certain embodiments, R is -OH.
  • R is of the Formula (i)
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR A , or -N(R B ) 2 ,
  • R A is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R is optionally substituted C 1-6 alkyl.
  • R 8 is unsubstituted Ci_ 6 alkyl.
  • R 8 is methyl or ethyl.
  • R 8 is optionally substituted phenyl.
  • R 8 is unsubstituted phenyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F. In certain embodiments, R 3 is CI. In certain embodiments, R 3 is Br. In certain embodiments, R 3 is I. In certain embodiments, R 3 is N0 2 . In certain embodiments, R 3 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted C 1-6 alkyl. In certain embodiments,
  • R 3 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 3 is substituted Ci_ 6 alkyl. In certain embodiments, R 3 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
  • R 3 is optionally substituted phenyl. In certain embodiments, R 3 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 3 is optionally substituted furanyl. In certain embodiments, R 3 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 3 is -OR A , wherein R A is as defined herein. In certain embodiments, R 3 is -OH. In certain embodiments, R 3 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is F. In certain embodiments, R 4 is CI. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is N0 2 . In certain embodiments, R 4 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 4 is substituted Ci_ 6 alkyl. In certain embodiments, R 4 is optionally substituted carbocyclyl. In certain embodiments, R 4 is optionally substituted cyclohexyl. In certain embodiments, R 4 is optionally substituted aryl. In certain
  • R 4 is optionally substituted phenyl. In certain embodiments, R 4 is optionally substituted heterocyclyl. In certain embodiments, R 4 is optionally substituted heteroaryl. In certain embodiments, R 4 is optionally substituted furanyl. In certain embodiments, R 4 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 4 is -OR A , wherein R A is as defined herein. In certain embodiments, R 4 is -OH. In certain embodiments, R 4 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • R 5 is hydrogen. In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is F. In certain embodiments, R 5 is CI. In certain embodiments, R 5 is Br. In certain embodiments, R 5 is I. In certain embodiments, R 5 is N0 2 . In certain embodiments, R 5 is optionally substituted alkyl. In certain embodiments, R 5 is optionally substituted C 1-6 alkyl. In certain embodiments, R 5 is unsubstituted C 1-6 alkyl. In certain embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 5 is substituted Ci_ 6 alkyl. In certain embodiments, R 5 is optionally substituted carbocyclyl. In certain embodiments, R 5 is optionally substituted cyclohexyl. In certain embodiments, R 5 is optionally substituted aryl. In certain embodiments,
  • R 5 is optionally substituted phenyl. In certain embodiments, R 5 is optionally substituted heterocyclyl. In certain embodiments, R 5 is optionally substituted heteroaryl. In certain embodiments, R 5 is optionally substituted furanyl. In certain embodiments, R 5 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 5 is -OR A , wherein R A is as defined herein. In certain embodiments, R 5 is -OH. In certain embodiments, R 5 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • At least one of R 4 and R 5 is halogen. In certain embodiments, one of R 4 and R 5 is halogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 5 is halogen. In certain embodiments, both R 4 and R 5 are halogen. In certain embodiments, at least one of R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, one of
  • R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, two of R 1 , R2 , and R 3 are not hydrogen. In certain embodiments, all R 1 , R2 , and R 3 are not hydrogen.
  • R 6 is hydrogen. In certain embodiments, R 6 is of the
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R is optionally substituted alkyl.
  • R 7 is optionally substituted Ci_ 6 alkyl.
  • R 7 is unsubstituted C 1-6 alkyl.
  • R is methyl, ethyl, n-propyl, or isopropyl.
  • R 7 is substituted C 1-6 alkyl. In certain embodiments, R 7 is optionally substituted carbocyclyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-(CH 2 )i_5- In certain embodiments, R is unsubstituted cyclopentyl-(CH 2 )i_5-. In certain embodiments,
  • R 7 is optionally substituted aryl. In certain embodiments, R 7 is optionally substituted phenyl.
  • R 7 is mono-substituted phenyl. In certain embodiments, R 7 is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments, R is optionally substituted 5-membered heteroaryl. In certain embodiments, R is optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3-furanyl.
  • the quinoline is of Formula (II):
  • the quinoline is of Formula (III):
  • the quinoline is of Formula (IV):
  • the quinoline is of Formula (V):
  • the quinoline is of any one of the compounds in Table
  • the quinoline is of any one of the compounds in Table
  • compositions or pharmaceutical compositions further comprise an additional therapeutically active agent.
  • additional therapeutically active agents include, but are not limited to, antibacterial agents (e.g. antibiotics), antiviral agents, fungicides, protozoacides, parasiticides, anesthetics, steroidal or non-steroidal anti-inflammatory agents, antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, prostaglandins, etc.
  • Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S. Food and Drug
  • the additional therapeutically active agent is an antimicrobial agent.
  • the additional therapeutically active agent is an antibacterial agent.
  • the antimicrobial agent is selected from the group consisting of biocides, fungicides, antibiotics, and mixtures thereof.
  • the antimicrobial agent is an antibiotic.
  • Exemplary antibacterial agents for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Florfenicol, Acetylsulfisoxazole,
  • Cephalosporins e.g., 7- Aminocephalosporanic acid, 7-Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine, Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin, Cephradine), Cetrimide Chelerythrine, Chlorhexidine, Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin
  • Clarithromycin Clavulanic acid (e.g., Amoxicillin-clavulanic acid), Clindamycin, Co- Trimoxazole, Dichlorophene, Didecyldimethylammonium chloride, Dihydrostreptomycin, Enoxacin, Ethambutol, Fleroxacin, Furazolidone, Grepafloxacin hydrochloride,
  • the additional therapeutically active agent is a fungicide.
  • fungicides for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Fumagillin, (-)-Metalaxyl, 1,2, 5-Fluorocytosine, Acrisorcin, Anilazine, Antifouling agents, Azoxystrobin, Benomyl, Bordeaux mixture, Captan, Carbendazim, Caspofungin acetate, Chlorothalonil, Clotrimazole, Dichlofluanid, Dinocap, Dodine, Fenhexamid, Fenpropimorph, Ferbam, Fluconazole, Fosetyl Al,
  • Griseofulvin Guanidines (e.g. Agmatine, Amiloride hydrochloride, Biguanides (e.g.
  • the additional therapeutically active agent is a protozoacide.
  • exemplary protozoacides for uses in combination with a quinoline as described herein include, but are not limited to, Amebicides, Antimalarials (e.g. Artemisinin,
  • Chloroquine e.g. Chloroquine phosphate
  • Mefloquine Mefloquine
  • Sulfadoxine Coccidiostats
  • Leishmanicides Trichomonacides
  • Trypanosomicides e.g. Eflornithine
  • the additional therapeutically active agent is an antibiotic.
  • antibiotics for uses in combination with a quinoline as described herein include, but are not limited to, Abamectin, Actinomycin (e.g. , Actinomycin A, Actinomycin C, Actinomycin D, Aurantin), Adriamycin, Alatrofloxacin mesylate, Amikacin sulfate, Aminosalicylic acid, Anthracyclines (e.g. , Aclarubicin, Adriamycin, Doxorubicin, Epirubicin, Idarubicin), Antimycin (e.g.
  • Cephalosporins e.g. , 7-Aminocephalosporanic acid, 7- Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine,
  • Cephalosporin C Cephalothin, Cephalothin sodium, Cephapirin, Cephradine
  • Ciprofloxacin Enrofloxacin
  • Clindamycin Colicin
  • Cyclosporin e.g. Cyclosporin A
  • Dalfopristin/quinupristin Daunorubicin
  • Neomycin sulfate e.g. 6-Aminopenicillanic acid, Amoxicillin (e.g. Amoxicillin- clavulanic acid), Ampicillin, Ampicillin sodium, Azlocillin, Carbenicillin, Cefoxitin, Cephaloridine, Cloxacillin, Dicloxacillin, Mecillinam, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin G potassium, Penicillin G procaine, Penicillin G sodium, Penicillin V, Piperacillin, Piperacillin-tazobactam, Sulbactam, Tazobactam, Ticarcillin), Phleomycin, Polymyxin (e.g., Colistin, Polymyxin B), Pyocin (e.g. Pyocin R), RPX 7009, Rapamycin, Ristocetin, Salinomycin, Sparfloxacin, Penicillin (e.g. 6-Aminopenicillanic acid,
  • Tetracyclines e.g. Achromycin V, Demeclocycline, Doxycycline, Doxycycline
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)
  • crospovidone sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers
  • colloidal clays e.g. , bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)
  • long chain amino acid derivatives e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. , carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. , carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. , polyoxyethylene sorbitan monolaurate (Tween 20),
  • polyoxyethylene sorbitan Teween 60
  • polyoxyethylene sorbitan monooleate Teween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g. , polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
  • sucrose fatty acid esters polyethylene glycol fatty acid esters (e.g. , CremophorTM), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamerl88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. , cornstarch and starch paste), gelatin, sugars (e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g. ,
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer' s solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quatern
  • the dosage form may comprise buffering agents.
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • the dosage form may comprise buffering agents.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical are Suitable devices for use in delivering intradermal pharmaceutical
  • compositions described herein include short needle devices.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal
  • inventive pharmaceutical compositions may also be mixed with blood ex vivo, and the resulting mixture may be administered (e.g. , intravenously) to a subject.
  • administration e.g. , intravenously
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g. , a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of the quinoline and potentiating agent described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of the quinoline and potentiating agent described herein.
  • a dose described herein includes independently between 3 mg and 10 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of the quinoline and potentiating agent described herein.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a dose described herein is a dose for an adult human whose body weight is approximately 70 kg.
  • the pharmaceutical composition as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the pharmaceutical compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • the one or more additional therapeutically active agents are different from the compounds and compositions described herein.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • it is expected that additional therapeutically active agents in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Exemplary additional therapeutically active agents also include, but are not limited to, cytotoxic agents. Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the present invention provides a kit for treating or preventing an infectious disease in a subject, wherein the kit comprising: a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject.
  • the present invention provides a kit for preventing biofilm formation in a subject, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject.
  • the present invention provides a kit for treating biofilm formation on an object, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical
  • composition to the object composition to the object.
  • the present invention provides a kit for eradicating a biofilm, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical composition to the object.
  • the present invention provides a kit comprising: a container comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof; and instructions for using the compound or pharmaceutical composition.
  • the kit is for treating or preventing an infectious disease in a subject.
  • the kit is for preventing biofilm formation in a subject.
  • the kit is for preventing biofilm formation on an object.
  • the kit is for reducing or eradicating biofilm in a subject.
  • the kit is for reducing or eradicating biofilm on an object.
  • the instructions are for administrating the compound or pharmaceutical composition in a subject.
  • the instructions are for applying the compound or pharmaceutical composition to an object.
  • kits provided may comprise a device, e.g., a vial, ampule, bottle, syringe, and/or dispenser, for administering or applying the pharmaceutical composition as described herein.
  • a device e.g., a vial, ampule, bottle, syringe, and/or dispenser, for administering or applying the pharmaceutical composition as described herein.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
  • the pharmaceutical composition described herein provided in the first container and the second container are combined to form one unit dosage form.
  • Infectious diseases are typically caused by microbial pathogens (e.g., viruses, viroids, prions, microorganisms such as bacteria, nematodes such as roundworms and pinworms, arthropods such as ticks, mites, fleas, and lice, fungi such as ringworm, and parasites such as protozoa, multicellular parasites, or tapeworms) into the cells ("host cells") of a subject ("host").
  • the infectious disease is a bacterial infection.
  • the infectious disease is a mycobacterial infection.
  • the infectious disease is a viral infection.
  • the infectious disease is a parasitic infection.
  • the infectious disease is a multicellular-parasitic infection.
  • the infectious disease is a fungal infection.
  • the infectious disease is a protozoan infection.
  • inventive methods for preventing and/or treating an infectious disease comprise administering to a subject in need thereof a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient.
  • the present invention provides methods for preventing an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the present invention provides methods for treating an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the infectious disease is responsive to the chelation or sequestration of a metal.
  • the metal is a monovalent, divalent, tetravalent, pentavalent, or hexavalent metal.
  • the metal is a monovalent metal.
  • the metal is a divalent metal.
  • the metal is a trivalent metal.
  • the metal is aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g.
  • the metal is iron (e.g. , Fe(II)). In certain embodiments, the metal is zinc (e.g. , Zn (II)). In certain embodiments, the metal is copper (e.g. Cu (II)).
  • the infectious disease being treated and/or prevented is a bacterial infection.
  • the bacterial infection being treated and/or prevented is a chronic bacterial infection.
  • a "chronic bacterial infection” is a bacterial infection that is of a long duration or frequent recurrence.
  • a chronic middle ear infection, or otitis media can occur when the Eustachian tube becomes blocked repeatedly due to allergies, multiple infections, ear trauma, or swelling of the adenoids.
  • the definition of "long duration" will depend upon the particular infection. For example, in the case of a chronic middle ear infection, it may last for weeks to months.
  • Exemplary chronic bacterial infections include, but are not limited to, urinary tract infection (most commonly caused by Escherichia coli and/or Staphylococcus saprophyticus), gastritis (most commonly caused by Helicobacter pylori), respiratory infection (such as those commonly afflicting patents with cystic fibrosis, most commonly caused by Pseudomonas aeuroginosa), cystitis (most commonly caused by Escherichia coli), pyelonephritis (most commonly caused by Proteus species, Escherichia coli and/or Pseudomonas sp), osteomyelitis (most commonly caused by Staphylococcus aureus, but also by Escherichia coli), bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones (can be caused by Proteus mirabilis), bacterial endocarditis, and sinus infection.
  • urinary tract infection most commonly caused by Escherichia
  • the bacterial infection is one or more infections selected from the group consisting of urinary tract infection, gastritis, respiratory infection, cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, and sinus infection.
  • the infectious diseases is pneumonia, urinary tract infection, complicated intra-abdominal infection, or complicated skin/skin structure infection.
  • the infectious diseases is nosocomial pneumonia, community- acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, or melioidosis.
  • the bacterial infection is respiratory infection.
  • the bacterial infection is upper respiratory infection. In certain embodiments, the bacterial infection is pneumonia. In certain embodiments, the bacterial infection is bronchitis.
  • the bacterial infection is caused by a Gram positive bacteria.
  • Gram positive bacteria include, but are not limited to, Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, and Corynebacterium.
  • the Gram positive bacteria is a bacteria of the phylum Firmicutes.
  • the bacteria is a member of the phylum
  • Enterococci bacteria include, but are not limited to, E. avium, E.
  • the Enterococcus infection is an E. faecalis infection. In certain embodiments, the Enterococcus infection is an E. faecium infection. In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus
  • Staphylococcus i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
  • the Staphylococcus infection is an S. aureus infection.
  • the Staphylococcus infection is an S. aureus infection.
  • Staphylococcus infection is an S. epidermis infection.
  • the bacterial infection is a Gram negative bacteria.
  • Exemplary Gram negative bacteria include, but are not limited to, Escherchia coli,
  • catarrhalis Citrobacter diversus, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhimurium, Neisseria meningitidis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Salmonella enteriditis,
  • the Gram negative bacteria species is Pseudomonas. In certain embodiments, the Gram negative bacteria species is Pseudomonas aeruginosa. In certain embodiments, the Gram negative bacteria species is Acinetobacter baumannii.
  • the bacterial infection being treated and/or prevented is caused by an organism resistant to one or more antibiotics.
  • the bacterium is resistant to penicillin.
  • the bacterium is resistant to vancomycin (VR).
  • the bacterium is vancomycin- resistant E. faecalis.
  • bacterium is vancomycin-resistant E. faecium.
  • bacterium is vancomycin-resistant Staphylococcus aureus (VRSA).
  • bacterium is vancomycin-resistant Enterococci (VRE).
  • the bacterium is a methicillin-resistant (MR) strain.
  • the bacterium is methicillin-resistant S. aureus (MRSA).
  • the bacterium is methicillin-resistant Staphylococcus epidermidis (MRSE).
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • the bacterium is penicillin-resistant Streptococcus pneumonia. In certain embodiments, the bacterium is quinolone-resistant Staphylococcus aureus (QRSA). In certain embodiments, the bacterium is multi-drug resistant Mycobacterium tuberculosis.
  • QRSA quinolone-resistant Staphylococcus aureus
  • the bacterium is susceptible to one or more antibiotics.
  • the gram-positive bacterium is susceptible to one or more antibiotics.
  • the gram- negative bacterium is susceptible to one or more antibiotics.
  • antibiotics include, but are not limited to beta-lactams, sulfonamides,
  • aminoglycosides aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides,
  • the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, aminoglycosides, tetracyclines, and quinolones.
  • the gram-positive bacterium is susceptible to methicillin.
  • the gram-negative bacterium is susceptible to one or more antibiotics selected from the group consisting of tigecycline, amikacin, ampicillin, and sulbactam.
  • bacterial susceptibility also called bacterial sensitivity, refers to inhibition of a bacterial growth by an antimicrobial agent when the recommended dosage is used for the site of infection.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition as described herein.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a
  • the biofilms are produced by one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae.
  • the biofilms are produced by bacteria.
  • the biofilms are produced by Gram-negative bacteria.
  • the biofilms are produced by microbial species such as S. epidermidis, E. faecalis, E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, S. aureus, S. viridans, K. oxytoca, S. saprophyticus, L. pneumophila,
  • biofilms are produced by Gram-positive bacteria.
  • a method for inhibiting bacterial cell growth comprising contacting bacteria with the pharmaceutical composition as described herein.
  • a method for inhibiting bacterial cell growth comprising contacting bacteria with a compound of Formula (C-I), or a
  • pharmaceutically acceptable salt solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with the pharmaceutical composition as described herein.
  • a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • Hypersusceptibility refers to a condition of abnormal susceptibility to poisons, infective agents, or agents that are entirely innocuous in the normal individual.
  • a method for preventing biofilm formation comprising contacting a subject with the pharmaceutical composition as described herein.
  • a method for preventing biofilm formation comprising contacting a subject with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • provided herein is a method for preventing biofilm formation comprising contacting an object with the pharmaceutical composition as described herein.
  • a method for preventing biofilm formation comprising contacting an object with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a method for eradicating biofilm comprising contacting the biofilm with the pharmaceutical composition as described herein.
  • a method for eradicating biofilm comprising contacting the biofilm with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the bacterium/a is contacted with the pharmaceutical composition as described herein in vitro. In certain embodiments, the bacterium/a is contacted with the pharmaceutical composition as described herein in vivo. In certain embodiments, the bacterium is subsequently contacted with one or more biocides. In certain embodiments, the biocides are antimicrobials. In certain embodiments, the antimicrobials are antibiotics.
  • the compounds of Formulae (I)-(V) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the compounds of Formulae (C-I) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily dosage of the compositions of the present invention will be decided by an attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient(s) employed; and like factors well known in the medical arts.
  • the compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents (e.g., antibiotics, anti-inflammatory agents).
  • additional therapeutically active agents e.g., antibiotics, anti-inflammatory agents
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the subject administered the quinoline as provided herein or pharmaceutical composition is a mammal.
  • the subject is a human.
  • the subject is immunodeficient.
  • Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent.
  • the subject is a patient diagnosed with cystic fibrosis.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal such as a dog or cat.
  • the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is an experimental animal such as a rodent or non-human primate.
  • the present invention provides methods to treat or prevent biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of chelating a metal (e.g. , quninoline) or pharmaceutical composition thereof as described herein.
  • the provided method treats, cleans, or disinfects a wound by administering the compound or composition as described herein.
  • the wounds are chronic wounds, acute wounds, surgical wounds, surgical sites, second and third degree burns, stasis ulcers, tropic lesions, decubitus ulcers, severe cuts, or abrasions.
  • the present invention provides methods to treat or prevent biofilm formation comprising contacting an object with an effective amount of a compound capable of chelating a metal (e.g. , quinoline) or the composition as described herein.
  • the provided methods inhibit, reduce, or remove biofilms on an object.
  • the provided method is to inhibit or remove the biofilm on the surface of the object.
  • the surface is a hard, rigid surface.
  • the surface is selected from the group consisting of a drainpipe, glaze ceramic, porcelain, glass, metal, wood, chrome, plastic, vinyl, and formica.
  • the surface is a soft, flexible surface.
  • the surface is selected from the group consisting of shower curtains or liners, upholstery, laundry, and carpeting.
  • the surface is a food preparation surface, such as kitchen counters, cutting boards, sinks, stoves, refrigerator surfaces, or on sponges.
  • the surface is a bathroom surface such as toilets, sinks, bathtubs, showers, and drains.
  • the surface is a medical device surface.
  • the contacting of the compound or composition as described herein with the object is carried out by wiping, sponging, or soaking, or laundering means.
  • the provided method is used to prevent or eradicate biofilm as a dentifrice, a mouthwash, a compound for the treatment of dental caries, acne treatment, cleaning and disinfecting contact lenses, and medically implanted devices that are permanent such as an artificial heart valve or hip joint, and those that are not permanent such as indwelling catheters, pacemakers, surgical pins etc.
  • the provided method is used to prevent or remove biofilm in situations involving bacterial infection of a host, either human or animal, for example in a topical dressing for burn patients. An example of such a situation would be the infection by P. aeruginosa of superficial wounds such as are found in burn patients or in the lung of a cystic fibrosis patient.
  • the provided method can be used to control or prevent the development of biofilm in the process of manufacturing integrated circuits, circuit boards or other electronic or microelectronic devices.
  • the invention also provides quinoline compounds of
  • each of R , R , and R is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, or optionally substituted acyl;
  • R is hydrogen, halogen, or -N0 2 ;
  • R 5E is hydrogen, halogen, or -N0 2 ;
  • R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group; and provided that R 4E is halogen or N0 2 .
  • R IE is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or optionally substituted acyl. In certain embodiments, R IE hydrogen. In certain embodiments, R IE is halogen. In certain embodiments, R IE is F. In certain embodiments, R IE is CI. In certain embodiments, R IE is Br. In certain embodiments,
  • R IE is I. In certain embodiments, R IE is optionally substituted C 1-6 alkyl. In certain embodiments, R IE is unsubstituted C 1-6 alkyl. In certain embodiments, R IE is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R IE is substituted Ci_ 6 alkyl. In certain embodiments, R IE is optionally substituted acyl.
  • R 2E is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or optionally substituted acyl. In certain embodiments, R 2E hydrogen. In certain embodiments, R 2E is halogen. In certain embodiments, R 2E is F. In certain embodiments, R 2E is CI. In certain embodiments, R 2E is Br. In certain embodiments,
  • R 2E is I. In certain embodiments, R 2E is optionally substituted C 1-6 alkyl. In certain embodiments, R 2E is unsubstituted C 1-6 alkyl. In certain embodiments, R 2E is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R 2E is substituted Ci_ 6 alkyl. In certain embodiments, R 2E is optionally substituted acyl.
  • R 2E is of the Formula (iii)
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR A , or -N(R B ) 2 ;
  • R A is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R 8E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR , or -N(R ) 2.
  • R is optionally substituted alkyl.
  • R 8E is optionally substituted C 1-6 alkyl.
  • R 8E is unsubstituted C 1-6 alkyl.
  • R 8E is methyl, ethyl, n- propyl, or isopropyl.
  • R 8E is optionally substituted carbocyclyl.
  • R 8E is optionally substituted cyclohexyl. In certain embodiments, R 8E is optionally substituted aryl. In certain embodiments, R 8E is optionally substituted phenyl. In certain embodiments, R 8E is optionally substituted heterocyclyl. In certain embodiments, R 8E is optionally substituted heteroaryl. In certain embodiments, R 8E is optionally substituted monocyclic heteroaryl. In certain embodiments, R 8E is optionally substituted 5-membered heteroaryl. In certain embodiments, R 8E is optionally substituted furanyl. In certain embodiments, R 8E is optionally substituted 2-furanyl or 3-furanyl.
  • R 3E is independently hydrogen, halogen, optionally substituted Ci_ 6 alkyl, or optionally substituted acyl. In certain embodiments, R 3E is hydrogen. In certain embodiments, R 3E is halogen. In certain embodiments, R 3E is F. In certain embodiments, R 3E is CI. In certain embodiments, R 3E is Br. In certain embodiments,
  • R 3E is I. In certain embodiments, R 3E is optionally substituted Ci_ 6 alkyl. In certain
  • R 3E is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 3E is methyl, ethyl, n- propyl, or isopropyl. In certain embodiments, R 3E is substituted C 1-6 alkyl. In certain embodiments, R 3E is optionally substituted acyl.
  • R 4E is hydrogen, halogen, or -N0 2 . In certain embodiments, R 4E is hydrogen. In certain embodiments, R 4E is halogen. In certain
  • R 4E is F. In certain embodiments, R 4E is CI. In certain embodiments, R 4E is Br.
  • R 4E is I. In certain embodiments, R 4E is N0 2 .
  • R 5E is hydrogen, halogen, or -N0 2 . In certain embodiments, R 5E is hydrogen. In certain embodiments, R 5E is halogen. In certain
  • R 5E is F. In certain embodiments, R 5E is CI. In certain embodiments, R 5E is Br.
  • R 5E is I. In certain embodiments, R 5E is N0 2 .
  • R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R 6E is hydrogen. In certain embodiments, R is optionally substituted acyl. In certain embodiments, R is an oxygen protecting group.
  • R 6E is Boc. In certain embodiments, R 6E is of the Formula (iv):
  • R 7E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R is optionally substituted alkyl.
  • R 7E is optionally substituted Ci_ 6 alkyl.
  • R 7E is unsubstituted C 1-6 alkyl.
  • R 7E is methyl, ethyl, n-propyl, or isopropyl.
  • R 7E is substituted C 1-6 alkyl. In certain embodiments, R 7E is optionally substituted carbocyclyl-alkyl. In certain embodiments, R 7E is optionally substituted
  • R is optionally substituted cyclopentyl-(CH 2 )i_5-
  • R is unsubstituted cyclopentyl-(CH 2 )i-5-. In certain embodiments,
  • R 7E is optionally substituted aryl. In certain embodiments, R 7E is optionally substituted phenyl.
  • R 7E is optionally substituted phenyl of the formula , wherein e is 0, 1, 2, 3, 4, or 5; R is independently selected from the group consisting of hydrogen, halogen, -CN, -N0 2 , -N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl.
  • e is 0.
  • e is 1.
  • e is 2.
  • e is 3.
  • e is 4.
  • e is 5.
  • e is 1 and R is optionally substituted alkyl or optionally substituted alkoxy.
  • e is 1 and R is one of the group consisting of hydrogen, halogen, -CN, -N0 2 , -N 3 , optionally substitute
  • e is 2 or
  • e is 3 and R 7E is one of the formulae:
  • e is 5 and R is of the formula
  • R is optionally substituted alkyl.
  • R E is nts, R is one of the
  • R is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments,
  • R is optionally substituted 5-membered heteroaryl. In certain embodiments, R 7 /E E i ⁇ s optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3 -furanyl.
  • a provided compound is any compound in Table 1.
  • a provided compound is any one of the compounds shown in Table 1, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof (e.g., compounds shown in Table 1, and pharmaceutically acceptable salts thereof).
  • MIC minimum inhibitory concentration
  • Staphylococcus aureus ATCC strains: 29213, BAA-1707; clinical isolates MRSA-1, MRSA-2, SA-156
  • Staphylococcus epidermidis ATCC 12228; clinical isolate MRSE-1
  • Acinetobacter baumannii ATCC strains: 19606, BAA-1794
  • Klebsiella pneumonia ATCC 13883
  • Pseudomonas aeruginosa PAOl
  • gallic acid combinations with conventional antibacterial agents including: ciprofloxacin (targets DNA gyrase/topoisomerase IV; inhibits DNA synthesis), methicillin (targets transpeptidase; inhibits cell wall synthesis), erythromycin (targets 50S subunit of ribosome; inhibits protein synthesis), tobramycin (targets 30S and 50S subunits of ribosome; inhibits protein synthesis) and vancomycin (targets pentapeptides; inhibits cell wall synthesis). None of these antibacterial agents were potentiated by GA. This result points to a unique antibacterial mechanism for quinoline compounds that differs from conventional antibiotics.
  • S. epidermidis Methicillin-susceptible ATCC 12228 strain was used in addition to a methicillin-resistant S. epidermidis (MRSE-1) clinical isolate. GA was found to have some antibacterial activities against these strains (MICs 469 and 625 ⁇ , respectively). About 250 ⁇ of GA was used in these potentiation assays (-1/2 MIC). The overall potentiation of exemplified quinoline compounds by GA was less dramatic against S. epidermidis (4- to 63- fold potentiation) compared to S. aureus, but 9 of 13 exemplified quinoline compounds (69%) tested in the panel were potentiated against both S. epidermidis strains.
  • the quinoline compounds-GA combination demonstrates good antibacterial activity for select exemplified quinoline compounds, including: 1 (MIC: >100 ⁇ ; MIC + GA: 9.38 ⁇ ), 4 (MIC: 25 ⁇ ; MIC + GA: 0.3 ⁇ ) and 5 (MIC: >100 ⁇ ; MIC + GA: 1.56 ⁇ ).
  • Ester quinoline compounds 20 and 21 also demonstrated GA potentiation similar to their free hydroxyl counterparts (20 with 4; 21 with 1), most likely through a prodrug esterase cleavage mechanism. These esters did provide slight increases in antibacterial potencies (with and without GA) compared to their corresponding hydroxyl quinoline compounds (1 and 4).
  • a panel of exemplified quinoline compounds in combination with GA were tested against the gram- negative pathogens P. aeruginosa (PAOl) and K. pneumoniae (ATCC 13883). No potentiation of antibacterial activity was observed with the exemplified quinoline compounds -GA combination against PAOl (MICs for all exemplified quinoline compounds > 100 ⁇ with and without GA). GA potentiation of some quinoline compounds were found against K. pneumoniae such as 1, 4, 5, 17 (nitroxoline), 20 and 21. Gallic Acid Potentiation of Halogenated Quinoline 1 in MRSA-2 Biofilm Eradication Assay:
  • a single colony grown on LB agar solid medium was amplified in 2 milliliters of tryptic soy broth (TSB) medium with 0.5% glucose to an OD 6 oo ⁇ 1-0.
  • the bacterial suspension was then diluted to -lxlO 6 CFUmL "1 in TSB with 0.5% glucose.
  • Sterile 96-well flat-bottomed polystyrene plates (0.1% gelatin coated overnight) were then filled with 100 ⁇ ⁇ of this bacterial suspension.
  • the microtiter plates were then covered and incubated for 24 hours at 37 °C.
  • test compound in 100 ⁇ ⁇ TSB 0.5% glucose were delivered into each well at concentrations ranging from 2 to 2,000 ⁇ (DMSO did not exceed 2% v/v in these assays).
  • Gallic acid i.e., potentiating agent
  • the plates were then covered with a lid, wrapped in saran wrap and incubated with test compounds for 24 hours at 37 °C.
  • biofilm eradication was determined accordingly (microtiter wells that were turbid resulted from live biofilm/bacterial growth while microtiter wells that had no turbidity resulted from completely eradicated biofilms).
  • Minimum Biofilm Eradication Concentration (MBEC) values were determined as the lowest concentration of a test compound that resulted in complete biofilm eradication.
  • 8-Hydroxyquinolines contain a metal binding motif which includes the phenolic oxygen and heterocyclic nitrogen atom of the quinoline ring which can chelate various metal(II) cations (V. Prachayasittikul, S. Prachayasittikul, S. Ruchirawat, V.
  • Zinc(II)-, iron(II)- and copper(II)-cations were added in potentiation assays in an analogous fashion to potentiating agents (i.e., gallic acid) in the potentiation protocol described above.
  • Metal(II)-cations used during these studies included: ZnCl 2 , (NH 4 ) 2 Fe(S0 4 ) 2 -6H 2 0 and CuS0 4 .
  • Zinc(II) chloride (at 100 ⁇ ; ⁇ l/7 MIC) was found to potentiate the antibacterial activities of quinoline compounds 4 and 5 by 21- and 83-fold, respectively.
  • 8-Hydroxyquinoline 18 and nitroxoline 17 do not possess any halogen atoms and were not potentiated by ZnCl 2 , but did follow iron(II) and copper(II) potentiation trends similar to the exemplified quinoline compounds.
  • CytoTox96 Promega G1780
  • HeLa cells were grown in Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% Fetal Bovine Serum (FBS) at 37°C with 5% C0 2 .
  • FBS Fetal Bovine Serum
  • halogenated quinolines were then diluted by DMEM (10% FBS) at concentrations of 25, 50 and 100 ⁇ and added to HeLa cells.
  • Triton X-100 (at 2% v/v) was used as the positive control for maximum lactate dehydrogenate (LDH) activity in this assay (i.e., complete cell death) while "medium only" lanes served as negative control lanes (i.e., no cell death).
  • LDH lactate dehydrogenate
  • DMSO DMSO was used as our vehicle control. HeLa cells were treated with compounds for 24 hours and then 50 of the supernatant was transferred into a fresh 96-well plate where 50 ⁇ ⁇ of the reaction mixture was added to the 96-well plate and incubated at room temperature for 30 minutes. Finally, 50 ⁇ L ⁇ of the Stop Solution is added to the incubating plates and the absorbance was measured at 490 nm.
  • the exemplified quinolines were evaluated for their abilities to inhibit bacterial growth in microdilution MIC experiments head-to-head against bromophenazine 1 (positive control) using a panel of four clinically relevant pathogens: S. aureus ATCC 29213, S. epidermidis ATCC 12228, A. baumannii ATCC 19606 and P. aeruginosa PAOl/BAA-47.
  • This panel of pathogens included both gram-positive (S. aureus and S. epidermidis) and gram-negative (A. baumannii and P. aeruginosa) bacteria to determine the spectrum of activity of the exemplified quinolines.
  • these quinolines were evaluated against several S. aureus clinical isolates, including several methicillin-resistant S. aureus isolates and a S. epidermidis clinical isolate.
  • aureus strain ATCC 29213 was used to obtain MIC and IC 50 values from same biofilm inhibition experiment (assay optimized for biofilm formation).
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

The present invention provides compositions comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable carrier, for treating and/or preventing infectious diseases. The provided compositions may also include another therapeutic agent (e.g., antibiotic). The provided compositions may be useful in treating and/or preventing bacterial infections as well as inhibiting and eradicating biofilm formation.

Description

COMBINATION THERAPY FOR TREATING INFECTIOUS DISEASES
RELATED APPLICATIONS
[0001] The present invention claims priority under 35 U.S.C. § 119(e) to U.S.
provisional patent application, U.S. S.N. 62/136,053, filed March 20, 2015, which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Infectious diseases are the third leading cause of death in developed countries and the second leading cause of death worldwide (see, e.g., World Health Organization (WHO) Geneva, World Health Report (2002); Nathan, Nature (2004) 431 :899). The efficacy of many antibacterial drugs has been compromised by the emergence of drug resistant, pathogenic bacteria (see, e.g., National Nosocomial Infections Surveillance (NNIS) System, Am. J. Infect. Control (2004) 32:470). The Infectious Disease Society of America has recently outlined the deadly implications of a growing number of drug-resistant pathogens (see, e.g., Boucher et ah, J. Clin. Infect. Dis. (2009) 48: 1). Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and penicillin-resistant Streptococcus epidermis are especially worrisome in clinical settings. Unfortunately, the prevalence of multidrug-resistant bacteria has made antibiotics of last resort, like vancomycin, the first-line of therapy. The capacity of bacteria to routinely develop resistance to virtually any antibacterial agent necessitates a continuous search for new drugs. There is much evidence in the literature that natural products derived from microorganisms will continue to be a source of novel antibacterial drugs (see, e.g., Clardy, Nat. Biotechnol. (2006) 24: 1541). Although natural products often have chemical properties that are incompatible with chemotherapy, it is possible to use medicinal chemistry as a means to enhance their biological activity and/or pharmacological properties (see, e.g., von Nussbaum et al., Angew. Chem. Int. Ed. (2006) 45:5072).
[0003] Biofilms are complex communities of microorganisms that are commonly found on a variety of substrates or surfaces that are moist or submerged (Musk et ah, Curr. Med. Chem., 2006, 13, 2163). Though primarily populated by bacteria, biofilms can also contain many different individual types of microorganisms, e.g., bacteria, archaea, protozoa, and algae. The formation of biofilms can be thought of as a developmental process in which a few free-swimming (planktonic) bacteria adhere to a solid surface and, in response to appropriate signals, initiate the formation of a complex sessile microcolony existing as a community of bacteria and other organisms. Bacteria within biofilms are usually embedded within a matrix, which can consist of protein, polysaccharide, nucleic acids, or combinations of these macromolecules. The matrix is a critical feature of the biofilm that protects the inhabiting organisms from antiseptics, microbicides, and host cells. It has been estimated that bacteria within biofilms are upwards of 1,000-fold more resistant to conventional antibiotics (Rasmussen et al., Int. J. Med. Microbiol., 2006, 296, 149). Accordingly, there is a need for development of new therapies to treat infectious diseases such as bacterial infections and/or biofilm.
SUMMARY OF THE INVENTION
[0004] The widespread use of antibiotics over the past several decades has accelerated the spread of drug-resistant bacteria (Antimicrobial resistance: global report on surveillance. World Health Organization. 2014, 1-257). This global health care crisis is amplified by the current state of the antibiotic pipeline which, since the late 1960's, has led to little success in bringing new antibiotics/antibacterial agents to the clinic (Payne et al., Nat. Rev. Drug Discov. 2007, 6, 29-40). The current antibiotic arsenal is mostly composed of natural product antibiotics and synthetic antibacterial agents that were originally discovered as bacterial growth inhibitors in whole-cell (phenotype) screens (Lewis, Nat. Rev. Drug Discov. 2013, 12, 371-387). As a result, the large majority of the antibiotic arsenal hits relatively few bacterial targets (e.g., cell wall synthesis machinery, bacterial ribosomes, DNA gyrase/topoisomerase, RNA polymerase) (K. Lewis, Nat. Rev. Drug Discov. 2013, 12, 371- 387).
[0005] With the rise of drug-resistant bacteria outpacing the development of new antibacterial agents, the discovery of antibacterial agents that operate via new modes of action and hit new bacterial targets is increasingly important. This rational led to extensive screening campaigns of promising antibacterial targets in the late 1990' s following the first complete sequencing of a bacterial genome (Haemophilus influenza) (Payne et al., Nat. Rev. Drug Discov. 2007, 6, 29-40). Despite much effort, target-based screens of large compound libraries have yet to bring a single antibacterial agent to market.
[0006] In one aspect, the present invention provides compositions comprising a quinoline and a potentiating agent, wherein the potentiating agent comprises a catechol moiety. In certain embodiments, the present invention provides compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiet and optionally a surfactant. The provided composition can be used to incorporate into, coat, impregnate, flush, or rinse an object or material. In certain embodiments, the composition is a cleaning composition. The provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm {e.g., tubing).
[0007] In certain embodiments, the present invention provides pharmaceutical compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiety, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the quinoline is a halogenated quinoline (HQ), i.e., comprising at least one halogen substituent. In certain embodiments, the quinoline comprises at least one -N02 substituent. In certain embodiments, the quinoline is a halogenated quinoline comprising at least one -N02 substitutent.
[0008] The potentiating agent acts to promote the antibacterial "potentiation" of the quinoline. The potentiating agent may lower the minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy. In certain embodiments, the potentiating agent is a phytochemical. As used herein, phytochemicals refer to chemical compounds that occur naturally in plants or are derived from plants. In certain embodiments, the potentiating agent is gallic acid, caffeic acid, or tiron. In certain embodiments, the potentiating agent is gallic acid.
[0009] In certain embodiments, the pharmaceutical composition further comprises a second antimicrobial agent such as an antibiotic. In certain embodiments, the pharmaceutical composition further comprises a salt. In certain embodiments, the salt is a metal (II) salt.
[0010] In certain embodiments, the the quinoline is of Formula (I):
Figure imgf000004_0001
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0011] In certain embodiments, the the quinoline is of Formula (II):
Figure imgf000004_0002
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0012] In certain embodiments, the the quinoline is of Formula (III):
Figure imgf000005_0001
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0013] In certain embodiments, the the quinoline is of Formula (IV):
Figure imgf000005_0002
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0014] In certain embodiments, the quinoline is of Formula (V):
Figure imgf000005_0003
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0015] In another aspect, the present invention provides a compound of Formula (C-
I):
Figure imgf000005_0004
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof.
[0016] In another aspect, the present invention provides methods to treat and/or prevent an infectious disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein. In certain embodiments, the infectious disease is a bacterial infection. In certain embodiments, the bacterial infection is a chronic bacterial infection. In certain embodiments, the bacterial infection is a urinary tract infection, gastritis, respiratory tract infection (e.g., those seen in patients with cystic fibrosis), cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, ear infection, and sinus infection. In certain embodiments, the bacterial infection is a Gram-negative bacterial infection. In certain embodiments, the Gram-negative bacterium is A. baumannii or K. pneumonia. In certain embodiments, the bacterial infection is a Gram-positive bacterial infection. In certain embodiments, the Gram-positive bacterium is S. aureus or S. epidermidis. In certain embodiments, the bacterium is an antibiotic-resistant strain. In certain embodiments, the bacterium is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE). In certain embodiments, the bacterium is an antibiotic-susceptible strain. In certain embodiments, the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, sulfonamides, aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides, oxazolidinones, ansamycins, quinolones, streptogramins, and lipopeptides. In certain embodiments, the subject having or susceptible to the infectious disease also contracts another disease or condition. In certain embodiments, the subject is diagnosed with cystic fibrosis.
[0017] In certain embodiments, the infectious disease is a fungal infection. In certain embodiments, the infectious disease is a parasital infection. In certain embodiments, the infectious disease is a protozoan infection. In certain embodiments, the infectious disease is associated with the formation of a biofilm.
[0018] In another aspect, the present invention provides methods for killing a bacterium comprising contacting the bacterium with a pharmaceutical composition as described herein.
[0019] In another aspect, the present invention provides methods for inhibiting bacterial cell growth comprising contacting the bacterium with a pharmaceutical composition as described herein.
[0020] In another aspect, the present invention provides methods for inducing bacterial hypersusceptibility comprising contacting a bacterium with a pharmaceutical composition as described herein. [0021] In another aspect, the present invention provides methods of preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
[0022] In another aspect, the present invention provides methods of eradicating a biofilm comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein. In certain embodiments, the biofilm includes one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae. In some embodiments, the biofilm includes bacteria.
[0023] In another aspect, the present invention provides methods of treating and/or preventing biofilm formation comprising contacting an object with an effective amount of the pharmaceutical composition as described herein. In certain embodiments, the provided method is useful in inhibiting and/or removing a biofilm on the surface of an object.
[0024] In certain embodiments, the biofilm is produced by an organism selected from the group consisting of bacteria, archaea, algae, fungi, and protozoa. In some embodiments, the biofilm is a bacterial biofilm. In certain embodiments, the biofilm includes antibiotic- resistant bacteria. In certain embodiments, the biofilm includes MRSA.
[0025] Without wishing to be bound by any particular theory, the quinoline in the provided pharmaceutical compositions (e.g. any one of Formulae (I)-(V)) may bind metal ions and thereby provide their antibacterial properties. In certain embodiments, the quinoline in the provided pharmaceutical compositions binds iron and/or other metals (e.g. , aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uranium)). In certain embodiments, the quinoline in the provided pharmaceutical compositions binds metal(II) ions. In certain embodiments, the metal (II) ion(s) is/are Zn2+, Fe2+, and/or Cu2+. In certain embodiments, the quinoline in the provided pharmaceutical compositions chelates Fe and one or more metals important for bacterial growth, e.g. K, Mg, Ca, Mn, Zn, Co, Cu, and Mo.
[0026] In yet another aspect, the invention provides a kit for treating and/or preventing an infectious disease. In yet another aspect, the invention provides a kit for preventing formation of biofilms. In yet another aspect, the invention provides a kit for eradicating biofilms. In certain embodiments, the kit is to treat and/or prevent biofilm formation in a subject. In certain embodiments, the kit is to treat and/or prevent biofilm formation on an object (e.g. surface). In certain embodiments, the kit further comprises an antimicrobial agent (e.g. , antibiotics). In certain embodiments, the inventive kits include a first container containing a therapeutically effective amount of a pharmaceutical composition as described herein, and instructions for administering the pharmaceutical composition to the subject to treat and/or prevent an infectious disease. In certain embodiments, the inventive kits include a first container containing an effective amount of a composition as described herein, and instructions for using the composition to prevent and/or eradicate a biofilm. In certain embodiments, the kit is a cleaning kit. In certain embodiments, the kit further comprises a disinfectant. A kit may also include multiple unit dosages, for example, for multiple days of treatment.
[0027] The details of one or more embodiments of the invention are set forth herein.
Other features, objects, and advantages of the invention will be apparent from the Detailed Description, Examples, and Claims.
DEFINITIONS
[0028] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March ' s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern
Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.
[0029] It is to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and those that are non-superimposable mirror images of each other are termed "enantiomer s". When a compound has an asymmetric center, for example, a carbon atom of the compound is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates plane polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture." For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and
Resolutions (Wiley Interscience, New York, 1981); Wilen et ah, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[0030] Where an isomer/enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched" or "enantiomerically enriched." "Optically enriched" and
"enantiomeric ally enriched" means that a provided compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, a compound of the present invention is made up of at least about 70% by weight of a preferred enantiomer. In certain embodiments, a compound of the present invention is made up of at least about 80% by weight of a preferred enantiomer. In certain embodiments, a compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid
chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and
Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
[0031] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the depicted structures that differ only in the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by 13C or 14C are within the scope of this invention. Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
[0032] In a formula, ·~»~ is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified,— is absent or a single bond, and = or is a single or double bond.
[0033] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "CiV is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci_6, Ci_5, Ci^, Ci_3, Ci_2, C2_6, C2_5, C2^, C2_3, C3_6, C3_5, C3^, C4_6, C4_5, and Cs_6.
[0034] The terms "purified," "substantially purified," and "isolated" refer to a compound useful in the present invention being free of other, dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, 20%, 50%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% of the mass, by weight, of a given sample or composition. In one embodiment, these terms refer to the compound comprising at least 95%, 98%, 99%, or 99.9% of the mass, by weight, of a given sample or composition.
[0035] The term "acyl" refers to a group having the general formula -C(=0)R , -
C(=0)ORxl, -C(=0)-0-C(=0)Rxl, -C(=0)SRxl, -C(=0)N(Rxl)2, -C(=S)RX1, - C(=S)N(RX1)2, and -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRxl)ORxl, -C(=NRX1)SRX1, and -
C(=NR XI )N(R XI )2, wherein R XI is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R XI groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-C02H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, hetero aliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0036] The term "aliphatic" includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, and cyclic (i.e. , carbocyclic)
hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl", and the like.
Furthermore, the terms "alkyl", "alkenyl", "alkynyl", and the like encompass both substituted and unsubstituted groups. In certain embodiments, "aliphatic" is used to indicate those aliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. Aliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy,
heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0037] The term "alkyl" refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. In some embodiments, the alkyl group employed in the invention contains 1-20 carbon atoms. In another embodiment, the alkyl group employed contains 1-15 carbon atoms. In another embodiment, the alkyl group employed contains 1-10 carbon atoms. In another embodiment, the alkyl group employed contains 1-8 carbon atoms. In another embodiment, the alkyl group employed contains 1-5 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl (e.g. , unsubstituted methyl (Me)), ethyl (e.g. , unsubstituted ethyl (Et)), propyl (e.g. , unsubstituted propyl (Pr)), n-propyl, isopropyl, butyl (e.g. , unsubstituted butyl (Bu)), n-butyl, z'so-butyl, sec -butyl, sec-pentyl, wo-pentyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like, which may bear one or more sustitutents. Alkyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0038] The term "alkenyl" denotes a monovalent group derived from a straight- or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. In certain embodiments, the alkenyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkenyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkenyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkenyl group contains 2-8 carbon atoms. In yet other embodiments, the alkenyl group contains 2-5 carbons. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten- 1-yl, and the like, which may bear one or more substituents. Alkenyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted). In an alkenyl group, e stereochemistry is not specified (e.g., -CH=CHCH3,
Figure imgf000012_0001
m me
(E)- or (Z)-configuration.
[0039] The term "alkynyl" refers to a monovalent group derived from a straight- or branched-chain hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. In certain embodiments, the alkynyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkynyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkynyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkynyl group contains 2-8 carbon atoms. In still other embodiments, the alkynyl group contains 2-5 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl
(propargyl), 1-propynyl, and the like, which may bear one or more substituents. Alkynyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy,
heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0040] Exemplary carbon atom substituents include, but are not limited to, halogen, -
CN, -N02, -N3, -S02H, -S03H, -OH, -OR^, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X , - N(ORcc)Rbb, -SH, -SR^, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -CO^, - OC(=0)Raa, -OCChR^, -C(=0)N(Rbb)2, -OC(=0)N(Rbb)2, -NRbbC(=0)Raa, -NR^CO^, - NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, - C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, - NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -SOsOR^, -OSO^, -S(=0)Raa, -OS(=0)Raa, - Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)2Raa, -OP(=0)2Raa, -P(=0)(Raa)2, - OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)2N(Rbb)2, -OP(=0)2N(Rbb)2, -P(=0)(NRbb)2, - OP(=0)(NRbb)2, -NRbbP(=0)(ORcc)2, -NRbbP(=0)(NRbb)2, -P(RCC)2, -P(RCC) , -OP(Rcc)2, - OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BR^OR^), Cno alkyl, Cno perhaloalkyl, C2-10 alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc; each instance of is, independently, selected from Cuo alkyl, Cuo perhaloalkyl, C2_io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered
heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -SO^, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, - S02N(Rcc)2, -S02Rcc, -S02ORcc, -SOR^, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, - Ρ(=0)^, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, Cno alkyl, Cno perhaloalkyl, C2 io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5- 14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, Ci_io alkyl, Cuo perhaloalkyl, C2_io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, - S02H, -S03H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X , -N(ORee)Rff, -SH, -SRee, - SSRee, -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, - OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, - OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, - NRffC(=NRff)N(Rff)2,-NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree, -S(=0)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)2Ree, - P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2 6 alkynyl, C3_io carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S;
each instance of Ree is, independently, selected from Ci_6 alkyl, Ci_6 perhaloalkyl, C2 6 alkenyl, C2_6 alkynyl, C3_io carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
ff
each instance of R is, independently, selected from hydrogen, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io carbocyclyl, 3-10 membered heterocyclyl, Ce- ff
io aryl and 5-10 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -S03H, - OH, -OCi_6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci_6 alkyl)2, -N(Ci_6 alkyl)3 +X- -NH(Ci_6 alkyl)2 +X~ -NH2(Ci_6 alkyl) +X~, -NH3 +X , -N(OCi_6 alkyl)(Ci_6 alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SCi-6 alkyl, -SS(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), -C02H, -C02(Ci^, alkyl),
Figure imgf000015_0001
alkyl), -OC02(Ci 6 alkyl), -C(=0)NH2, -C(=0)N(Ci_6 alkyl)2, - OC(=0)NH(Ci_6 alkyl), -NHC(=0)( Ci_e alkyl), -N(Ci_6 alkyl)C(=0)( Ci_6 alkyl), - NHC02(Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl)2, -NHC(=0)NH(Ci 6 alkyl), -NHC(=0)NH2, - C(=NH)0(Ci^, alkyl),-OC(=NH)(Ci_6 alkyl), -OC(=NH)OCi_6 alkyl, -C(=NH)N(Ci_6 alkyl)2, -C(=NH)NH(Ci_6 alkyl), -C(=NH)NH2, -OC(=NH)N(Ci_6 alkyl)2, -OC(NH)NH(Ci_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(Ci_6 alkyl)2, -NHC(=NH)NH2, -NHS02(Ci_6 alkyl), - S02N(Ci_6 alkyl)2, -S02NH(Ci^, alkyl), -S02NH2,-S02Ci^, alkyl, -S02OCi_6 alkyl, - OS02Ci^, alkyl, -SOCi_6 alkyl, -Si(Ci^, alkyl)3, -OSi(Ci_6 alkyl)3 -C(=S)N(Ci_6 alkyl)2, C(=S)NH(Ci_6 alkyl), C(=S)NH2, -C(=0)S(Ci_6 alkyl), -C(=S)SCi_6 alkyl, -SC(=S)SCi_6 alkyl, -P(=0)2(Ci^, alkyl), -P(=0)(Ci_6 alkyl)2, -OP(=0)(Ci_6 alkyl)2, -OP(=0)(OCi_6 alkyl)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S; wherein X is a counterion.
[0041] In certain embodiments, exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORaa, -ON(Rbb)2,
-N(Rbb)2, -N(Rbb)3 +X", -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, -OC(=0)Raa, -OC02Raa, -C(=0)N(Rbb)2, -OC(=0)N(Rbb)2,
-NRbbC(=0)Raa, -NR^COsR^, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2,
-NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa,
-S02ORaa, -OS02Raa, -S(=0)Raa, -OS(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)(Raa)2, -P(=0)(ORcc)2, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)(N(Rbb)2)2, -OP(=0)(N(Rbb)2)2, -NRbbP(=0)(Raa)2, -NRbbP(=0)(ORcc)2,
-NRbbP(=0)(N(Rbb)2)2, -P(RCC)2, -P(ORcc)2, -P(RCC)3 +X", -P(ORcc)3 +X", -P(RCC)4,
-P(ORcc)4, -OP(Rcc)2, -OP(Rcc)3 +X", -OP(ORcc)2, -OP(ORcc)3 +X", -OP(Rcc)4, -OP(ORcc)4, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), Ci_i0 alkyl, C 0 perhaloalkyl, C2_i0 alkenyl, C2_i0 alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X~ is a counterion;
or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc; each instance of is, independently, selected from CMO alkyl, Ci_io perhaloalkyl, C2_io alkenyl, C2_io alkynyl, heteroCi_io alkyl, heteroC2_ioalkenyl, heteroC2_ioalkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa,
-N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -CC^R^, -SC^R^, -C(=NRcc)ORaa,
-C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SOR^, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -P(=0)(Raa)2, -P(=0)(ORcc)2, -P(=0)(N(Rcc)2)2, CMO alkyl, CM0 perhaloalkyl, C2_io alkenyl, C2-1o alkynyl, heteroCi-ioalkyl, heteroC2_ioalkenyl, heteroC2_ioalkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X~ is a counterion;
each instance of Rcc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C2_io alkenyl, C2_io alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X", -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2,
-OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2,
-NRffC(=NRff)N(Rff)2, -NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree,
-S(=0)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)(ORee)2, -P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6alkyl, heteroC2_6alkenyl, heteroC2_6alkynyl, C3_io carbocyclyl, 3-10 membered heterocyclyl, C6 io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S; wherein X~ is a counterion;
each instance of Ree is, independently, selected from Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6 alkyl, heteroC2_6alkenyl, heteroC2_6 alkynyl, C3_io
carbocyclyl, C6 io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
each instance of R ff is, independently, selected from hydrogen, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6alkyl, heteroC2_6alkenyl, heteroC2_6alkynyl, C3_io carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OCi_6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci_6 alkyl)2, -N(Ci_6 alkyl)3 +X-, -NH(Ci_6 alkyl)2 +X", -NH2(Ci_6 alkyl) +X", -NH3 +X", -N(OCi_6 alkyl)(Ci_6 alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SCi_6 alkyl, -SS(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), -C02H, -C02(Ci_6 alkyl), -OC(=0)(Ci_6 alkyl), -OC02(Ci_6 alkyl), -C(=0)NH2, -C(=0)N(Ci_6 alkyl)2, -OC(=0)NH(Ci_6 alkyl), -NHC(=0)( Ci_6 alkyl), -N(Ci_6 alkyl)C(=0)( Ci_6 alkyl),
-NHC02(Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl)2, -NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci_6 alkyl), -OC(=NH)(Ci_6 alkyl), -OC(=NH)OCi_6 alkyl, -C(=NH)N(Ci_6 alkyl)2, -C(=NH)NH(Ci_6 alkyl), -C(=NH)NH2, -OC(=NH)N(Ci_6 alkyl)2, -OC(NH)NH(Ci_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(Ci_6 alkyl)2, -NHC(=NH)NH2, -NHS02(Ci_6 alkyl), -S02N(Ci_6 alkyl)2, -S02NH(Ci_6 alkyl), -S02NH2, -S02Ci_6 alkyl, -S02OCi_6 alkyl, -OS02Ci_6 alkyl, -SOCi_6 alkyl, -Si(Ci_6 alkyl)3, -OSi(Ci_6 alkyl)3 -C(=S)N(Ci_6 alkyl)2, C(=S)NH(Ci_6 alkyl), C(=S)NH2, -C(=0)S(Ci_6 alkyl), -C(=S)SCi_6 alkyl, -SC(=S)SCi_6 alkyl, -P(=0)(Od_6 alkyl)2, -P(=0)(d_6 alkyl)2, -OP(=0)(d_6 alkyl)2, -OP(=0)(Od_6 alkyl)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6alkyl, heteroC2_ 6alkenyl, heteroC2-6alkynyl, C3_io carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S;
wherein X~ is a counterion.
[0042] The term "amino" refers to a group of the formula (-NH2). A "substituted amino" refers either to a mono-substituted amine (-NHRh) of a disubstituted amine (-NRh 2), wherein the Rh substituent is any substituent as described herein that results in the formation of a stable moiety (e.g., a suitable amino protecting group; aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, amino, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted). In certain embodiments, the Rh substituents of the disubstituted amino group(-NRh 2) form a 5- to 6-membered heterocyclic ring.
[0043] The term "alkoxy" refers to a "substituted hydroxyl" of the formula (-OR1), wherein R1 is an optionally substituted alkyl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
[0044] The term "alkylthioxy" refers to a "substituted thiol" of the formula (-SRr), wherein Rr is an optionally substituted alkyl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
[0045] The term "alkylamino" refers to a "substituted amino' Of the formula (-NRh 2), wherein Rh is, independently, a hydrogen or an optionally substituted alkyl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule. [0046] The term "aryl" refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which all the ring atoms are carbon, and which may be substituted or unsubstituted. In certain embodiments of the present invention, "aryl" refers to a mono, bi, or tricyclic C4-C2o aromatic ring system having one, two, or three aromatic rings which include, but not limited to, phenyl, biphenyl, naphthyl, and the like, which may bear one or more substituents. Aryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0047] The term "arylalkyl" refers to an aryl substituted alkyl group, wherein the terms "aryl" and "alkyl" are defined herein, and wherein the aryl group is attached to the alkyl group, which in turn is attached to the parent molecule. Exemplary arylalkyl groups are benzyl and phenethyl.
[0048] The term "aryloxy" refers to a "substituted hydroxyl" of the formula (-OR1), wherein R1 is an optionally substituted aryl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
[0049] The term "arylamino," refers to a "substituted amino' Of the formula (-NRh 2), wherein Rh is, independently, a hydrogen or an optionally substituted aryl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
[0050] The term "arylthioxy" refers to a "substituted thiol" of the formula (-SRr), wherein Rr is an optionally substituted aryl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
[0051] The term "carbonyl" refers a group wherein the carbon directly attached to the parent molecule is sp hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g. , a group selected from ketones (-C(=0)Raa), carboxylic acids (-C02H), aldehydes (- CHO), esters (-CO^, -C(=0)SRaa, -C(=S)SRaa), amides (-C(=0)N(Rbb)2, - C(=0)NRbbS02Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), - C(=NRbb)N(Rbb)2), wherein Raa and Rbb are as defined herein.
[0052] The terms "halo" and "halogen" refer to an atom selected from fluorine
(fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I). [0053] The term "heteroaliphatic" refers to an aliphatic moiety, as defined herein, which includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, cyclic (i.e. , heterocyclic), or polycyclic hydrocarbons, which are optionally substituted with one or more functional groups, and that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms. In certain
embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more substituents. As will be appreciated by one of ordinary skill in the art, "heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. Thus, the term "heteroaliphatic" includes the terms
"heteroalkyl," "heteroalkenyl", "heteroalkynyl", and the like. Furthermore, the terms
"heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass both substituted and unsubstituted groups. In certain embodiments, "heteroaliphatic" is used to indicate those heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. Heteroaliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0054] The term "heteroalkyl" refers to an alkyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
[0055] The term "heteroalkenyl" refers to an alkenyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
[0056] The term "heteroalkynyl" refers to an alkynyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms. [0057] The term "heteroalkylamino" refers to a "substituted amino" of the formula (-
NRh 2), wherein Rh is, independently, a hydrogen or an optionally substituted heteroalkyl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
[0058] The term "heteroalkyloxy" refers to a "substituted hydroxyl" of the formula (-
OR1), wherein R1 is an optionally substituted heteroalkyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
[0059] The term "heteroalkylthioxy" refers to a "substituted thiol" of the formula (-
SRr), wherein Rr is an optionally substituted heteroalkyl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
[0060] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3_i4 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C3_io carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3_8 carbocyclyl"). In some embodiments, carbocyclyl group has 3 to 7 ring carbon atoms ("C3_7 carbocyclyl"). In some embodiments, carbocyclyl group has 3 to 6 ring carbon atoms ("C3_6 carbocyclyl"). In some embodiments, carbocyclyl group has 4 to 6 ring carbon atoms ("C4_6 carbocyclyl"). In some embodiments, carbocyclyl group has 5 to 6 ring carbon atoms ("Cs_6 carbocyclyl"). In some embodiments, carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl"). Exemplary C3_6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3_8 carbocyclyl groups include, without limitation, the aforementioned C3_6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3_io carbocyclyl groups include, without limitation, the
aforementioned C3_8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3_i4 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3_i4 carbocyclyl.
[0061] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3_i4 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3_io cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3_8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl"). Examples of Cs_6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3_8 cycloalkyl groups include the aforementioned C3_6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3_i4 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3_i4 cycloalkyl.
[0062] The term "heterocyclic," "heterocycles," or "heterocyclyl" refers to a cyclic heteroaliphatic group. A heterocyclic group refers to a non-aromatic, partially unsaturated or fully saturated, 3- to 12-membered ring system, which includes single rings of 3 to 8 atoms in size, and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or heteroaryl groups fused to a non-aromatic ring. These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Heterocyclyl groups include, but are not limited to, a bi- or tri-cyclic group, comprising fused five, six, or seven- membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Exemplary heterocycles include azacyclopropanyl, azacyclobutanyl, 1,3-diazatidinyl, piperidinyl, piperazinyl, azocanyl, thiaranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, thiacyclohexanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, dioxanyl, oxathiolanyl, morpholinyl, thioxanyl, tetrahydronaphthyl, and the like, which may bear one or more substituents. Substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0063] The term "heteroaryl" refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryls include, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, quinazolynyl, phthalazinyl, naphthridinyl,
quinoxalinyl, thiophenyl, thianaphthenyl, furanyl, benzofuranyl, benzothiazolyl, thiazolynyl, isothiazolyl, thiadiazolynyl, oxazolyl, isoxazolyl, oxadiaziolyl, oxadiaziolyl, and the like, which may bear one or more substituents. Heteroaryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0064] The term "heteroarylamino" refers to a "substituted amino' Of the (-NRh 2), wherein Rh is, independently, hydrogen or an optionally substituted heteroaryl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
[0065] The term "heteroaryloxy" refers to a "substituted hydroxyl" of the formula (-
OR1), wherein R1 is an optionally substituted heteroaryl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
[0066] The term "heteroarylthioxy" refers to a "substituted thiol" of the formula (-
SRr), wherein Rr is an optionally substituted heteroaryl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
[0067] The term "hydroxy" or "hydroxyl" refers to a group of the formula (-OH). A
"substituted hydroxyl" refers to a group of the formula (-OR1), wherein R1 can be any substituent which results in a stable moiety (e.g., a suitable hydroxyl protecting group;
aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, nitro, alkylaryl, arylalkyl, and the like, each of which may or may not be further substituted).
[0068] The term "nitro" refers to a group of the formula (-N02).
[0069] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR2121, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -SO^, -C(=NRbb)Raa, -C(=NRcc)ORaa,
-C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SOR^, -C(=S)N(RCC)2, -C(=0)SRcc -C(=S)SRCC, -P(=0)(ORcc)2, -P(=0)(Raa)2, -P(=0)(N(Rcc)2)2, C1-10 alkyl, CM0 perhaloalkyl, C2_io alkenyl, C2-1o alkynyl, heteroCi-ioalkyl, heteroC2_ioalkenyl, heteroC2_ioalkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein.
[0070] A "protecting group" is well known in the art and include those described in detail in Greene 's Protective Groups in Organic Synthesis, P. G. M. Wuts and T. W. Greene, 4 edition, Wiley-Interscience, 2006, the entirety of which is incorporated herein by reference. Suitable "amino-protecting groups" (also referred to as "nitrogen protecting groups") include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo- 10,10, 10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l, l-dimethyl-2-haloethyl carbamate, l, l-dimethyl-2,2- dibromoethyl carbamate (DB-i-BOC), l, l-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)- l- methylethyl carbamate (i-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, i-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), /?-methoxybenzyl carbamate (Moz), /?-nitobenzyl carbamate, /?-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-( ?-toluenesulfonyl)ethyl carbamate, [2-(l,3- dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m- chloro-/?-acyloxybenzyl carbamate, /?-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl- (lO)-carbonyl derivative, N'-/?-toluenesulfonylaminocarbonyl derivative, N'- phenylaminothiocarbonyl derivative, i-amyl carbamate, S-benzyl thiocarbamate, p- cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, /?-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l, l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1, 1-dimethylpropynyl carbamate, di(2- pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, /?-(/ -methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1- cyclopropylmethyl carbamate, 1 -methyl- 1 -(3, 5-dimethoxyphenyl)ethyl carbamate, 1-methyl- l-( ?-phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, /?-(phenylazo)benzyl carbamate, 2,4,6-tri-i- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, /?-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3- p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'- oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Ν,Ν'- isopropylidenediamine, N-/?-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or
tungsten)carbonyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S ), benzylsulfonamide,
trifluoromethylsulfonamide, and phenacylsulfonamide. In certain embodiments, nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=0)Raa,
-C(=0)N(Rcc)2, -C02Raa, -SO^, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SOR^, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, Ci_i0 alkyl (e.g., aralkyl, heteroaralkyl), C2_io alkenyl, C2_io alkynyl, heteroCi-io alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5- 14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein.
[0071] In certain embodiments, the substituent present on an oxygen atom is an hydroxyl protecting group. A "hydroxyl protecting group" (also referred to as an "oxygen protecting group") is well known in the art and includes those described in detail in Greene (1999). In certain embodiments, oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, -C(=0)Raa, -CO^, -C(=0)N(Rbb)2, -C(=NRbb)Raa,
-C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -SO^, -Si(Raa)3, -P(RCC)2, -P(RCC)3 +X", -P(ORcc)2, -P(ORcc)3 +X", -P(=0)(Raa)2, -P(=0)(ORcc)2, and -P(=0)(N(Rbb) 2)2, wherein X", R1^, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.
Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference. Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), /?-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), i-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4 -methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S ,S -dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1 -methyl- 1-benzyloxyethyl, 1 -methyl- 1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, /?-chlorophenyl, /?-methoxyphenyl, 2,4-dinitrophenyl, benzyl, /?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, /?-nitrobenzyl, /?-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, /?-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,
diphenylmethyl, /?,/ -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, /?-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri( ?-methoxyphenyl)methyl, 4-(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4 '-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4 '-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4',4 '-dimethoxyphenyl)methyl, 1, 1- bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),
diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, i-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-/?-xylylsilyl, triphenylsilyl,
diphenylmethylsilyl (DPMS), i-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl /?-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl /?-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl /?-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy- l-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(l, l,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l, l- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl Ν,Ν,Ν',Ν'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2- or 1,3-diols, protecting groups include methylene acetal, ethylidene acetal, 1-i-butylethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide,
cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p- methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, \-{N,N- dimethylamino)ethylidene derivative, a-(N,N'-dimethylamino)benzylidene derivative, 2- oxacyclopentylidene ortho ester, di-i-butylsilylene group (DTBS), 1,3-(1, 1,3,3- tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-i-butoxydisiloxane- l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.
[0072] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, -C(=0)Raa, -C02Raa, - C(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -SO^, - Si(Raa)3 -P(RCC)2, -P(RCC) , -Ρ(=0)^, -P(=0)(Raa)2, -P(=0)(ORcc)2, -P(=0)2N(Rbb)2, and - P(=0)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. In certain embodiments, sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, -C(=0)Raa, -C02Raa, -C(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -SOsR^, -Si(Raa)3, -P(RCC)2, -P(RCC)3 +X", -P(ORcc)2, -P(ORcc)3 +X~, -P(=0)(Raa)2, -P(=0)(ORcc)2, and -P(=0)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0073] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions {e.g. , F , CF, Br , Γ), N03 , C104 , OH , H2P04 , HC03 ~ HS04 , sulfonate ions (e.g. , methansulfonate, trifluoromethanesulfonate, /?-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g. , acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4 ~, PF4 , PF6 , AsF6 ~, SbF6 , B[3,5- (CF3)2C6H3]4r, B(C6F5)4 ", BPh4 , Al(OC(CF3)3)4 ~ and carborane anions (e.g. , CB nHi2 or
— 2— 2—
(HCBnMe5Br6) ). Exemplary counterions which may be multivalent include C03 , HP04 ,
3— 2— 2— 2—
P04 , B407 , S04 , S203 , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
[0074] The term "carbohydrate" or "saccharide" refers to an aldehydic or ketonic derivative of polyhydric alcohols. Carbohydrates include compounds with relatively small molecules (e.g. , sugars) as well as macromolecular or polymeric substances (e.g. , starch, glycogen, and cellulose polysaccharides). The term "sugar" refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates. Most monosaccharides can be represented by the general formula CyH2yOy (e.g., C6Hi206 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3. Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides. For example, deoxyribose is of the formula CsHio04 and is a monosaccharide. Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively. If the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose. Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively. Examples of aldotetrose sugars include erythrose and threose; and ketotetrose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. Each carbon atom of a monosaccharide bearing a hydroxyl group (-OH), with the exception of the first and last carbons, is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Because of this asymmetry, a number of isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula C6Hi206, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e. , 24) possible stereoisomers. The assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar. The aldehyde or ketone group of a straight- chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form. During the conversion from the straight-chain form to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring. The resulting possible pair of stereoisomers is called anomers. In an a anomer, the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the - CH2OH side branch. The alternative form, in which the -C¾OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a β anomer. A carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g. , a trisaccharide), respectively. The two or more monosaccharide units bound together by a covalent bond known as a glycosidic linkage formed via a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from another. Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, and rutinose. Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
[0075] The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate
(besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, /rara-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. "Basic addition salts" refer to salts derived from appropriate bases, these salts including alkali metal, alkaline earth metal, and quaternary amine salts. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like. Basic addition salts can be prepared during the final isolation and purification of the compounds, often by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium (by using, e.g. , NaOH), potassium (by using, e.g. , KOH), calcium (by using, e.g. , Ca(OH)2), magnesium (by using, e.g. , Mg(OH)2 and magnesium acetate), zinc, (by using, e.g. , Zn(OH)2 and zinc acetate), and aluminum, as well as nontoxic quaternary amine cations such as ammonium,
tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone, imidazole, n-methyl-d-glucamine, Ν,Ν'- dibenzylethylenediamine, N,A^-diethylethanolamine, N,A^-dimethylethanolamine, triethanolamine, and tromethamine. Basic amino acids (e.g. , 1-glycine and 1-arginine) and amino acids which may be zwitterionic at neutral pH (e.g. , betaine (N,N,N-trimethylglycine)) are also contemplated.
[0076] The term "tautomer" refers to a particular isomer of a compound in which a hydrogen and double bond have changed position with respect to the other atoms of the molecule. For a pair of tautomers to exist there must be a mechanism for interconversion. Examples of tautomers include keto-enol forms, imine-enamine forms, amide-imino alcohol forms, amidine-aminidine forms, nitroso-oxime forms, thio ketone-enethiol forms, N-nitroso- hydroxyazo forms, nitro-acz-nitro forms, lactam-lactim forms, ketene-ynol forms, enamine- enamine forms, and pyridione-hydroxypyridine forms.
[0077] The term "polymorphs" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
[0078] The term "solvate" refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of the invention may be prepared, e.g. , in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates, and methanolates.
[0079] The term "hydrate" refers to a compound that is associated with water.
Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R xH20, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g. , monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g. , hemihydrates (R 0.5H2O)), and polyhydrates (x is a number greater than 1, e.g. , dihydrates (R-2H20) and hexahydrates (R-6H20)).
[0080] The term "subject" refers to any animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human (e.g., a man, a woman, or a child). The human may be of either sex and may be at any stage of development. In certain embodiments, the subject has been diagnosed with the condition or disease to be treated. In other embodiments, the subject is at risk of developing the condition or disease. In certain embodiments, the subject is an experimental animal (e.g. , mouse, rat, rabbit, dog, pig, or primate). The experimental animal may be genetically engineered. In certain embodiments, the subject is a domesticated animal (e.g. , dog, cat, bird, horse, cow, goat, sheep).
[0081] The terms "administer," "administering," or "administration" refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.
[0082] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition" (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [0083] The terms "condition," "disease," and "disorder" are used interchangeably.
[0084] An "effective amount" of a compound of the present invention or a pharmaceutical composition thereof refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.
[0085] In certain embodiments, an effective amount is a cleaning-effective amount.
The "cleaning-effective" amount of the compound refers to an amount of the compound as described herein which is necessary to remove at least 10% of bacteria from a biofilm as determined by a reduction in numbers of bacteria within the biofilm when compared with a biofilm not exposed to the compound. In certain embodiments, the effective amount is a prophylactically effective amount to prevent normal biofilm formation between normal cleaning times as determined by a statistically significant increase in the number of cells within a biofilm or upon a clean surface. Prevention of normal biofilm formation is determined by the ability to disperse a biofilm using surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm. To distinguish between normal biofilm formation and treatment with a prophylactically effective amount of the compound as described herein, the treated biofilm must be shown to release 10% or more of its bacteria when compared with a similar biofilm that is not treated when both biofilms are exposed to surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm.
[0086] A "therapeutically effective amount" of a compound of the present invention or a pharmaceutical composition thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, e.g., iron overload, or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for chelating a metal described herein. In certain
embodiments, a therapeutically effective amount is an amount sufficient for treating a pathological condition described herein. In certain embodiments, a therapeutically effective amount is an amount sufficient for chelating a metal described herein and for treating a pathological condition described herein.
[0087] A "prophylactically effective amount" of a compound of the present invention is an amount sufficient to prevent a condition, e.g. , iron overload, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for chelating a metal described herein. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a pathological condition described herein. In certain embodiments, a prophylactically effective amount is an amount sufficient for chelating a metal described herein and for preventing a pathological condition described herein.
[0088] The term "biological sample" refers to any sample including tissue samples
(such as tissue sections and needle biopsies of a tissue); cell samples (e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
[0089] "Chelation," "chelating," "sequestration," or "sequestering" is the formation or presence of two or more separate coordinate bonds between a polydentate (multiple- bonded) compound and a single central atom. The polydentate compound is typically an organic compound and referred to as a "chelator," "chelant," "chelating agent,"
"sequestrator," "sequestering agent," or "ligand." The central atom is usually a metal atom or metal ion (e.g., a metal atom or metal ion described herein, such as iron (e.g., Fe(II)), Zn(II), and Cu (II), etc.). The chelator may form a stable complex with the central atom through coordinate bonds, inactivating the central atom so that the central atom is less likely to react with other molecules or atoms.
[0090] The term "antimicrobial" refers to a compound or composition having a destructive killing action upon microbes or microorganisms.
[0091] The term "microorganism" refer to very minute, microscopic life forms or organisms, which may be either plant or animal, and which may include, but are not limited to, algae, bacteria, fungi, protozoae, and parasites.
[0092] The term "biofilm formation" refers to the attachment of microorganisms to surfaces and the subsequent development of multiple layers of cells. In certain embodiments, the biofilm is bacterial biofilm.
[0093] The term "fungicide" refers to a compound or composition having either a fungicidal or fungistatic effect upon fungi contacted by the compound or comosition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0094] Figure 1 shows exemplary quinoline compounds useful in the present invention.
[0095] Figures 2 A to 2B show (Figure 2A) Friedlander quinoline synthesis used to synthesize quinolines 8-11; and (Figure 2B) structures of exemplified potentiating agents.
[0096] Figures 3A to 3D show (Figure 3A) antibacterial potentiation of quinolin compounds 1, 21 and 22 with GA against S. aureus 29213; (Figure 3B) biofilm eradication potentiation of quinoline compound 1 with Gallic Acid against MRSA-2; (Figure 3C) Metal(II) cation potentiation with 5 against S. aureus 29213; and (Figure 3D) kill curves for quinoline compound 1 and GA as single agents and in combination against S. aureus 29213.
[0097] Figure 4 shows a potentiation of antibacterial activity assay (determined by
MIC comparison).
[0098] Figure 5 shows kill kinetics for quinoline 1 against S. aureus 29213 to make final concentrations of 2x, 4x, and 16x MIC for quinoline 1.
[0099] Figure 6 shows kill kinetics for halogenated quinoline 1 against S. aureus
29213 8x MIC for quinoline compound 1 and vancomycin at 8x MIC.
[00100] Figure 7 shows cytotoxicity results of exemplary quinoline compounds
(Triton-X = 100% cell death; Medium Only: 0% cell death). Data represents mean + SD, (n=4). *P<0.05, **0.001 P<0.01, ***P<0.001, ns = non- significant, comparing with
"Medium Only" group.
[00101] Figure 8 shows exemplary quinoline potentiation with various phytochemicals against S. aureus (ATCC 29213) and cytotoxicity against HeLa cells, a = average of 2-fold range of MIC values. S.I. = selectivity index; IC50/MIC values to show antibacterial selectivity.
[00102] Figure 9 shows exemplary quinoline potentiation with gallic acid (GA) against methicillin-resistant S. aureus clinical isolates.
[00103] Figure 10 shows exemplary quinoline potentiation with gallic acid against S. epidermidis, A. baumannii and K. pneumoniae, a = average of 2-fold range of MIC values. * = partial reduction in turbidity observed; Strains: S. epidermidis (ATCC 12228), MRSE-1 (methicillin-resistant Staphylococcus epidermidis clinical isolate), A. baumannii (ATCC 19606), MDR A. baumannii (ATCC BAA-1794), K. pneumoniae (ATCC 13883).
[00104] Figure 11 shows metal(II) cation (100 μΜ) potentiation studies with quinolines against Staphylococcus aureus ATCC 29213. a = average of 2-fold range of MIC values, b = lowest concentration tested. * = partial reduction in turbidity at highest test concentrations.
[00105] Figure 12 shows gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
[00106] Figure 13 shows additional gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
[00107] Figure 14 shows caffeic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
[00108] Figure 15 shows tiron potentiation of antibacterial activity against S. aureus
ATCC 29213.
[00109] Figure 16 shows gallic acid potentiation of antibacterial activity against
MRSA-1.
[00110] Figure 17 shows gallic acid potentiation of antibacterial activity against
MRSA-2.
[00111] Figure 18 shows gallic acid potentiation of antibacterial activity against S. aureus BAA-1707 and gallic acid potentiation of antibacterial activity against SA-156 (MRS A). [00112] Figure 19 shows gallic acid potentiation of antibacterial activity against S. epidermidis ATCC 12228 and gallic acid potentiation of antibacterial activity against S. epidermidis MRSE-1.
[00113] Figure 20 shows gallic acid potentiation of antibacterial activity against
Acinetobacter baumannii ATCC 19606 and gallic acid potentiation of antibacterial activity against Acinetobacter baumannii BAA-1794.
[00114] Figure 21 shows gallic acid potentiation of antibacterial activity against
Klebsiella pneumoniae ATCC 13883 and gallic acid potentiation of antibacterial activity against Pseudomonas aeruginosa (PAOl).
[00115] Figure 22 shows ZnCl2-mediated potentiation of antibacterial activity against
S. aureus ATCC 29213.
[00116] Figure 23 shows (NH4)Fe(S04)2-mediated potentiation of antibacterial activity against S. aureus ATCC 29213.
[00117] Figure 24 shows CuS04-mediated potentiation of antibacterial activity against
S. aureus ATCC 29213.
[00118] Figure 25A shows evaluation of exemplary quinoline compounds in MRSA-2 biofilm dispersion assay; Figure 25B shows evaluation of exemplary quinoline compounds in S. epidermidis biofilm dispersion assay; Figure 25C shows dose-response curve for compound A2 against MRSA-2 biofilm.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[00119] Infectious diseases are caused by microbes such as bacteria, fungi, and parasites. These pathogenic micobes typically require one or more metals (e.g., iron, calcium, magnesium, strontium, potassium, sodium, chromium, copper, manganese, molybdenum, zinc, and tungsten) to sustain life. Without wishing to be bound by any particular theory, the inventive pharmaceutical compositions comprising a quinoline compound, a potentiating agent, and optionally a pharmaceutically acceptable excipient, can be used in the treatment and/or prevention infectious diseases. The quinoline compounds in the provided
compositions may act as metal chelators to interrupt the bacterial growth. Further provided herein are methods of using the provided pharmaceutical compositions to prevent or treat infectious disease. Also provided herein are methods of using the provided pharmaceutical compositions to prevent or eradicate biofilms. Compositions and Kits
[00120] In one aspect, the invention also provides a composition comprising a quinoline and a potentiating agent. In some embodiments, the invention provides a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the quinoline is a
halogenated quinoline, i.e. comprising at least one halogen substituent. In certain
embodiments, the quinoline comprises at least one N02 substituent. In certain embodiments, the quinoline is a halogenated quinoline comprising at least one N02 substitutent. In certain embodiments, the quinoline is a compound of any one of Formulae (I)-(V) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof. Also provided herein arepharmaceutical compositions comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a compound of Formula (C-I), or a pharmaceutically acceptable salt thereof).
[00121] The potentiating agent acts to promote the antibacterial "potentiation" of the quinoline. The potentiating agent may lower minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy. In certain embodiments, the potentiating agent is a phytochemical. As used herein,
phytochemicals refer to chemical compounds that occur naturally in plants. Exemplary phytochemicals include, but are not limited to, alkaloids (e.g. caffeine, theobromine, or theophylline), anthocyanins (e.g. cyanidin or malvidin), carotenoids (e.g. beta-carotene, lutein, or lycopene), coumestans, flavan-3-ols, flavonoids (e.g. epicatechin, hesperidin, isorhamnetin, kaempferol, myricetin, naringin, nobiletin, proanthocyanidins , quercetin, rutin, or tangeretin), hydroxycinnamic acids (e.g. chicoric acid, coumarin, ferulic acid, scopoletin, isoflavones, daidzein, or genistein), lignans (e.g. silymarin), monophenols (e.g.
hydroxytyrosol), monoterpenes (e.g. geraniol, limonene, organosulfides, allicin, glutathione, indole-3-carbinol, isothiocyanates, or sulforaphane), damnacanthal, digoxin, phytic acid, phenolic acids (e.g. capsaicin, ellagic acid, gallic acid, rosmarinic acid, tannic acid), phytosterols, beta-sitosterol, saponins, stylbenes (e.g. pterostilbene, resveratrol),
triterpenoids, ursolic acid, xanthophylls, astaxanthin, and beta-cryptoxanthin.
[00122] In certain embodiments, the potentiating agent comprises a catechol moiety.
As used herein, a catechol moiety refers to an optionally substituted, 1,2-dihydroxybenzyl moiety of the formula:
Figure imgf000041_0001
. it is understood that the catechol moiety also encompass derivatives of 1,2-dihydroxybenzyl. For example, the derivatives of 1,2-dihydroxybenzyl can include additional substituents on the phenyl ring and/or protecting groups on one or two of the hydroxyl groups. In certain embodiments, the catechol moiety is of the formula:
Figure imgf000041_0002
, wherein ca is 0, 1, 2, or 3, each instance of Rca is independently hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, - C(=0)Rc, -C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, - NRBC(=0)ORA, -NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2, wherein
R A , R B , and R C" are as defined herein. In certain embodiments, the potentiating agent is gallic acid, caffeic acid, or tiron. In certain embodiments, the potentiating agent is gallic acid.
[00123] In certain embodiments, the potentiating agent is present at about 1/100 of its
MIC. In certain embodiments, the potentiating agent is present at about 1/60 of its MIC. In certain embodiments, the potentiating agent is at about 1/30 of its MIC. In certain
embodiments, the potentiating agent is at about 1/20 of its MIC. In certain embodiments, the potentiating agent is at about 1/10 of its MIC. In certain embodiments, the potentiating agent is at about 1/8 of its MIC. In certain embodiments, the potentiating agent is at about 1/7 of its MIC. In certain embodiments, the potentiating agent is at about 1/6 of its MIC. In certain embodiments, the potentiating agent is at about 1/5 of its MIC. In certain embodiments, the potentiating agent is at about 1/4 of its MIC. In certain embodiments, the potentiating agent is at about 1/3 of its MIC. In certain embodiments, the potentiating agent is at about 1/2 of its MIC. In certain embodiments, the potentiating agent is at about 1/1 of its MIC.
[00124] In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 1010: 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 106: 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 105:1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 104: 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 100: 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10: 1 to about 1 : 1.
[00125] In certain embodiments, the quinoline is provided in an effective amount in the composition. In certain embodiments, the combination of quinoline and the potentiating agent is provided in an effective amount in the composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic ally effective amount. In certain embodiments, the effective amount is a clean-effective amount. In certain embodiments, the effective amount is to prevent biofilm formation. In certain embodiments, the effective amount is to eradicate or remove biofilm formed. In certain embodiments, the provided composition further comprises a surfactant. In certain embodiments, the surfactant is selected from the group consisting of anionic, nonionic, amphoteric, biological surfactants, and mixtures thereof. In certain embodiments, the provided composition further comprises one or more disinfecting agents. Disinfecting agents can comprise alcohols (such as ethanol or isopropanol), aldehydes (such as glutaraldehyde), oxidizing agents (such as sodium hypochlorite, calcium hypochlorite, chloramine, hydrogen peroxide, iodine, peracetic acid, performic acid, potassium
permanganate, and postassium peroxymonosulfate), phenolics (such as phenol, o- phenylphenol, chloroxylenol, hexachlorophene, and thymol). A disinfectant can be a spray or a liquid. A disinfectant can be concentrated or ready-to-use. A disinfectant can be for commercial or household use. A composition of the invention can also be incorporated into household disinfectants, laundry detergent, and household cleaning solutions.
[00126] In certain embodiments, the provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm (e.g. tubing). Therefore, in some embodiments, a method of the invention includes rinsing or decontaminating a surface by contacting the surface with a composition of the invention. Further, in some embodiments, a method of the invention includes inhibiting biofilm growth or preventing biofilm growth by incorporating, coating, impregnating, flusing, or rinsing an object with the provided composition. In some embodiments, a composition of the invention can be incorporated into a surface by coating or impregnating the surface of an object. [00127] In certain embodiments, the uinoline is of Formula (I):
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof,
wherein
each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, -C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2;
each instance of RA is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur;
each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; each instance of R is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
[00128] In certain embodiments, R1 is hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, - C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is halogen. In certain embodiments, R1 is F. In certain embodiments, R1 is CI. In certain embodiments, R1 is Br. In certain embodiments, R1 is I. In certain embodiments, R1 is N02. In certain embodiments, R1 is optionally substituted alkyl. In certain embodiments, R1 is optionally substituted Ci_6 alkyl. In certain embodiments, R1 is unsubstituted C1-6 alkyl. In certain embodiments, R1 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R1 is substituted C1-6 alkyl. In certain embodiments, R1 is optionally substituted carbocyclyl. In certain embodiments, R1 is optionally substituted cyclohexyl. In certain embodiments, R1 is optionally substituted aryl. In certain
embodiments, R1 is optionally substituted phenyl. In certain embodiments, R1 is optionally substituted heterocyclyl. In certain embodiments, R1 is optionally substituted heteroaryl. In certain embodiments, R1 is optionally substituted furanyl. In certain embodiments, R1 is optionally substituted 2-furanyl or 3 -furanyl. In certain embodiments, R1 is -ORA. In certain embodiments, R 1 is -OH. In certain embodiments, R 1 is -C(=0)R c . In certain embodiments,
R I is -C(=0)RC , wherein RC is optionally substituted alkyl or optionally substituted phenyl.
In certain embodiments, R I is -C(=0)RC , wherein RC is methyl, ethyl, or unsubstituted phenyl.
[00129] In certain embodiments, R is hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, - C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2. In certain embodiments,
R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is F. In certain embodiments, R 2 is CI. In certain embodiments, R 2 is Br. In certain embodiments, R 2 is I. In certain embodiments, R 2 is N02. In certain embodiments, R 2 is optionally substituted alkyl. In certain embodiments, R is optionally substituted C1-6 alkyl. In certain embodiments,
R 2 is unsubstituted C1-6 alkyl. In certain embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 2 is substituted Ci_6 alkyl. In certain embodiments, R 2 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
embodiments, R 2 is optionally substituted phenyl. In certain embodiments, R 2 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 2 is optionally substituted furanyl. In certain embodiments, R 2 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R2 is -ORA, wherein RA is as defined herein. In certain embodiments, R is -OH.
[00130] In certain embodiments, R is of the Formula (i)
Figure imgf000045_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORA, or -N(RB)2,
RA is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and
each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
[00131] In certain embodiments, R is optionally substituted C1-6 alkyl. In certain embodiments, R 8 is unsubstituted Ci_6 alkyl. In certain embodiments, R 8 is methyl or ethyl. In certain embodiments, R 8 is optionally substituted phenyl. In certain embodiments, R 8 is unsubstituted phenyl.
[00132] In certain embodiments, R is hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, - C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2. In certain embodiments,
R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F. In certain embodiments, R 3 is CI. In certain embodiments, R 3 is Br. In certain embodiments, R 3 is I. In certain embodiments, R 3 is N02. In certain embodiments, R 3 is optionally substituted alkyl. In certain embodiments, R1 is optionally substituted C1-6 alkyl. In certain embodiments,
R 3 is unsubstituted Ci_6 alkyl. In certain embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 3 is substituted Ci_6 alkyl. In certain embodiments, R 3 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
embodiments, R 3 is optionally substituted phenyl. In certain embodiments, R 3 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 3 is optionally substituted furanyl. In certain embodiments, R 3 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R3 is -ORA, wherein RA is as defined herein. In certain embodiments, R 3 is -OH. In certain embodiments, R 3 is -
C(=0)R C", wherein R C" is as defined herein. In certain embodiments, R 3 is -C(=0)R C , wherein
R C is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R 3 is -C(=0)R c , wherein R c is methyl, ethyl, or unsubstituted phenyl.
[00133] In certain embodiments, R4 is hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, - C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. In certain embodiments, R4 is F. In certain embodiments, R4 is CI. In certain embodiments, R4 is Br. In certain embodiments, R4 is I. In certain embodiments, R4 is N02. In certain embodiments, R4 is optionally substituted alkyl. In certain embodiments, R1 is optionally substituted C1-6 alkyl. In certain embodiments, R4 is unsubstituted Ci_6 alkyl. In certain embodiments, R4 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R4 is substituted Ci_6 alkyl. In certain embodiments, R4 is optionally substituted carbocyclyl. In certain embodiments, R4 is optionally substituted cyclohexyl. In certain embodiments, R4 is optionally substituted aryl. In certain
embodiments, R4 is optionally substituted phenyl. In certain embodiments, R4 is optionally substituted heterocyclyl. In certain embodiments, R4 is optionally substituted heteroaryl. In certain embodiments, R4 is optionally substituted furanyl. In certain embodiments, R4 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R4 is -ORA, wherein RA is as defined herein. In certain embodiments, R4 is -OH. In certain embodiments, R4 is -
C(=0)R C", wherein R C" is as defined herein. In certain embodiments, R 4 is -C(=0)R C , wherein
R C is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R 4 is -C(=0)R c , wherein R c is methyl, ethyl, or unsubstituted phenyl.
[00134] In certain embodiments, R5 is hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, - C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2. In certain embodiments, R5 is hydrogen. In certain embodiments, R5 is halogen. In certain embodiments, R5 is F. In certain embodiments, R5 is CI. In certain embodiments, R5 is Br. In certain embodiments, R5 is I. In certain embodiments, R5 is N02. In certain embodiments, R5 is optionally substituted alkyl. In certain embodiments, R5 is optionally substituted C1-6 alkyl. In certain embodiments, R5 is unsubstituted C1-6 alkyl. In certain embodiments, R5 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R5 is substituted Ci_6 alkyl. In certain embodiments, R5 is optionally substituted carbocyclyl. In certain embodiments, R5 is optionally substituted cyclohexyl. In certain embodiments, R5 is optionally substituted aryl. In certain
embodiments, R5 is optionally substituted phenyl. In certain embodiments, R5 is optionally substituted heterocyclyl. In certain embodiments, R5 is optionally substituted heteroaryl. In certain embodiments, R5 is optionally substituted furanyl. In certain embodiments, R5 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R5 is -ORA, wherein RA is as defined herein. In certain embodiments, R5 is -OH. In certain embodiments, R5 is -
C(=0)R C", wherein R C" is as defined herein. In certain embodiments, R 5 is -C(=0)R C , wherein
R C is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R 5 is -C(=0)R c , wherein R c is methyl, ethyl, or unsubstituted phenyl.
[00135] In certain embodiments, at least one of R4 and R5 is halogen. In certain embodiments, one of R4 and R5 is halogen. In certain embodiments, R4 is halogen. In certain embodiments, R5 is halogen. In certain embodiments, both R4 and R5 are halogen. In certain embodiments, at least one of R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, one of
R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, two of R 1 , R2 , and R 3 are not hydrogen. In certain embodiments, all R 1 , R2 , and R 3 are not hydrogen.
[00136] In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is of the
Formula (ii):
Figure imgf000047_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
[00137] In certain embodiments, R is optionally substituted alkyl. In certain embodiments, R 7 is optionally substituted Ci_6 alkyl. In certain embodiments, R 7 is unsubstituted C1-6 alkyl. In certain embodiments, R is methyl, ethyl, n-propyl, or isopropyl.
In certain embodiments, R 7 is substituted C1-6 alkyl. In certain embodiments, R 7 is optionally substituted carbocyclyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-(CH2)i_5- In certain embodiments, R is unsubstituted cyclopentyl-(CH2)i_5-. In certain embodiments,
R 7 is optionally substituted aryl. In certain embodiments, R 7 is optionally substituted phenyl.
In certain embodiments, R 7 is mono-substituted phenyl. In certain embodiments, R 7 is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments, R is optionally substituted 5-membered heteroaryl. In certain embodiments, R is optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3-furanyl.
[00138] In certain embodiments, the quinoline is of Formula (II):
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof.
[00139] In certain embodiments, the quinoline is of Formula (III):
Figure imgf000048_0002
or a pharmaceutically acceptable salt thereof.
[00140] In certain embodiments, the quinoline is of Formula (IV):
Figure imgf000048_0003
or a pharmaceutically acceptable salt thereof.
[00141] In certain embodiments, the quinoline is of Formula (V):
Figure imgf000048_0004
or a pharmaceutically acceptable salt thereof. ertain embodiments, the quinoline is of any one of the compounds in Table
Table 1. Exemplified Quinoline Compounds
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
[00143] In certain embodiments, the quinoline is of any one of the compounds in Table
1, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof (e.g., compounds in Table 1, and pharmaceutically acceptable salts thereof).
[00144] In certain embodiments, the provided compositions or pharmaceutical compositions further comprise an additional therapeutically active agent. Exemplary additional therapeutically active agents include, but are not limited to, antibacterial agents (e.g. antibiotics), antiviral agents, fungicides, protozoacides, parasiticides, anesthetics, steroidal or non-steroidal anti-inflammatory agents, antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, prostaglandins, etc. Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S. Food and Drug
Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, and vitamins. [00145] In certain embodimetns, the additional therapeutically active agent is an antimicrobial agent. In certain embodiments, the additional therapeutically active agent is an antibacterial agent. In certain embodimetns, the antimicrobial agent is selected from the group consisting of biocides, fungicides, antibiotics, and mixtures thereof. In certain embodimetns, the antimicrobial agent is an antibiotic.
[00146] Exemplary antibacterial agents for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Florfenicol, Acetylsulfisoxazole,
Actinonin, Amikacin sulfate, Benzethonium chloride, Cephalosporins (e.g., 7- Aminocephalosporanic acid, 7-Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine, Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin, Cephradine), Cetrimide Chelerythrine, Chlorhexidine(e.g. , Chlorhexidine gluconate), Chlorhexidine acetate, Chlorhexidine gluconate, Chlorothalonil, Ciprofloxacin (e.g., Enrofloxacin),
Clarithromycin, Clavulanic acid (e.g., Amoxicillin-clavulanic acid), Clindamycin, Co- Trimoxazole, Dichlorophene, Didecyldimethylammonium chloride, Dihydrostreptomycin, Enoxacin, Ethambutol, Fleroxacin, Furazolidone, Grepafloxacin hydrochloride,
Levofloxacin, Linezolid, Lomefloxacin, Methylisothiazolinone, Monolaurin, Oxolinic acid, Pefloxacin, Penicillin (e.g., 6-Aminopenicillanic acid, Amoxicillin (e.g., Amoxicillin- clavulanic acid), Ampicillin, Ampicillin sodium, Azlocillin, Carbenicillin, Cefoxitin, Cephaloridine, Cloxacillin, Dicloxacillin, Mecillinam, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin G potassium, Penicillin G procaine Penicillin G sodium, Penicillin V, Piperacillin, Piperacillin-tazobactam, Sulbactam, Tazobactam, Ticarcillin), Povidone-iodine, Rotproofing agents, Salinomycin, Sparfloxacin, Spirocheticides (e.g., Arsphenamine, Neoarsphenamine), Sulbactam, Sulfaquinoxaline, Tetracyclines (e.g., Achromycin V, Demeclocycline, Doxycycline, Doxycycline monohydrate, Minocycline, Oxytetracycline, Oxytetracycline hydrochloride, Tetracycline, Tetracycline hydrochloride), Thiamphenicol, Tinidazole, Triclosan, Trovafloxacin, Tuberculostatics (e.g., 4- Aminosalicylic acid, AZD 5847, Aminosalicylic acid, Ethionamide), Vidarabine, Zinc pyrithione, Zirconium phosphate.
[00147] In certain embodiments, the additional therapeutically active agent is a fungicide. Exemplary fungicides for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Fumagillin, (-)-Metalaxyl, 1,2, 5-Fluorocytosine, Acrisorcin, Anilazine, Antifouling agents, Azoxystrobin, Benomyl, Bordeaux mixture, Captan, Carbendazim, Caspofungin acetate, Chlorothalonil, Clotrimazole, Dichlofluanid, Dinocap, Dodine, Fenhexamid, Fenpropimorph, Ferbam, Fluconazole, Fosetyl Al,
Griseofulvin, Guanidines (e.g. Agmatine, Amiloride hydrochloride, Biguanides (e.g.
Imidodicarbonimidic diamide, Ν,Ν-dimethyl-, hydrochloride (l : l)(e.g. Metformin
hydrochloride), Metformin), Cimetidine, Guanethidine, Guanfacine, Guanidine,
Guanidinium, Methylguanidine, Sulfaguanidine), Iprobenfos, Iprodione, Isoprothiolane, Itraconazole, Ketoconazole, Mancozeb, Metalaxyl, Metiram, Miconazole, Natamycin, Nystatin, Oxycarboxine, Pentachloronitrobenzene, Prochloraz, Procymidone, Propiconazole, Pyrazophos, Reduced viscotoxin A3, Salicylanilide, Tebuconazole, Terbinafine,
Thiabendazole, Thiophanate, Thiophanate methyl, Triadimefon, Vinclozolin, Voriconazole.
[00148] In certain embodiments, the additional therapeutically active agent is a protozoacide. Exemplary protozoacides for uses in combination with a quinoline as described herein include, but are not limited to, Amebicides, Antimalarials (e.g. Artemisinin,
Chloroquine (e.g. Chloroquine phosphate), Mefloquine, Sulfadoxine), Coccidiostats, Leishmanicides, Trichomonacides, Trypanosomicides (e.g. Eflornithine).
[00149] In certain embodiments, the additional therapeutically active agent is an antibiotic. Exemplary antibiotics for uses in combination with a quinoline as described herein include, but are not limited to, Abamectin, Actinomycin (e.g. , Actinomycin A, Actinomycin C, Actinomycin D, Aurantin), Adriamycin, Alatrofloxacin mesylate, Amikacin sulfate, Aminosalicylic acid, Anthracyclines (e.g. , Aclarubicin, Adriamycin, Doxorubicin, Epirubicin, Idarubicin), Antimycin (e.g. , Antimycin A), Avermectin, BAL 30072, Bacitracin, Bleomycin, Cephalosporins (e.g. , 7-Aminocephalosporanic acid, 7- Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine,
Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin, Cephradine), Ciprofloxacin (Enrofloxacin), Clarithromycin, Clavulanic acid (Amoxicillin-clavulanic acid), Clindamycin, Colicin, Cyclosporin (e.g. Cyclosporin A), Dalfopristin/quinupristin, Daunorubicin,
Doxorubicin, Epirubicin, GSK 1322322, Geneticin, Gentamicin, Gentamicin sulfate, Gramicidin (e.g. Gramicidin A), Grepafloxacin hydrochloride, Ivermectin, Kanamycin (e.g. Kanamycin A), Lasalocid, Leucomycin, Levofloxacin, Linezolid, Lomefloxacin, Lovastatin, MK 7655, Meropenem, Mevastatin, Mithramycin, Mitomycin, Monomycin, Natamycin, Neocarzinostatin, Neomycin (e.g. Neomycin sulfate), Nystatin, Oligomycin, Olivomycin, Pefloxacin, Penicillin (e.g. 6-Aminopenicillanic acid, Amoxicillin (e.g. Amoxicillin- clavulanic acid), Ampicillin, Ampicillin sodium, Azlocillin, Carbenicillin, Cefoxitin, Cephaloridine, Cloxacillin, Dicloxacillin, Mecillinam, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin G potassium, Penicillin G procaine, Penicillin G sodium, Penicillin V, Piperacillin, Piperacillin-tazobactam, Sulbactam, Tazobactam, Ticarcillin), Phleomycin, Polymyxin (e.g., Colistin, Polymyxin B), Pyocin (e.g. Pyocin R), RPX 7009, Rapamycin, Ristocetin, Salinomycin, Sparfloxacin, Spectinomycin, Spiramycin,
Streptogramin, Streptovaricin, Tedizolid phosphate, Teicoplanin, Telithromycin,
Tetracyclines (e.g. Achromycin V, Demeclocycline, Doxycycline, Doxycycline
monohydrate, Minocycline, Oxytetracycline, Oxytetracycline hydrochloride Tetracycline, Tetracycline hydrochloride), Trichostatin A, Trovafloxacin, Tunicamycin, Tyrocidine, Valinomycin.
[00150] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
[00151] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
[00152] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.
[00153] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
[00154] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
[00155] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)
(crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
[00156] Exemplary surface active agents and/or emulsifiers include natural emulsifiers
(e.g. , acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. , bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g. , stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. , carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. , carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. , polyoxyethylene sorbitan monolaurate (Tween 20),
polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g. , polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. , Cremophor™), polyoxyethylene ethers, (e.g. , polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamerl88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
[00157] Exemplary binding agents include starch (e.g. , cornstarch and starch paste), gelatin, sugars (e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
[00158] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
[00159] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
[00160] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
[00161] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
[00162] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [00163] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
[00164] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
[00165] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.
[00166] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[00167] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
[00168] Liquid dosage forms for oral and parenteral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. , cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
[00169] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer' s solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00170] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00171] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be
accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
[00172] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
[00173] While it may be possible for the compounds disclosed herein, or
pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates, or
polymorphs thereof, to be administered orally as they are, it is also possible to present them as a pharmaceutical formulation or dosage. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium
compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.
[00174] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00175] The active ingredient can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes.
[00176] Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
[00177] Suitable devices for use in delivering intradermal pharmaceutical
compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. [00178] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
[00179] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
[00180] Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
[00181] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
[00182] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable
composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
[00183] A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
[00184] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
[00185] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical xz compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific
therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
[00186] The pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g. , systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct
administration to an affected site. The inventive pharmaceutical compositions may also be mixed with blood ex vivo, and the resulting mixture may be administered (e.g. , intravenously) to a subject. In general the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
[00187] The exact amount of the pharmaceutical composition required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g. , single oral dose) or multiple doses (e.g. , multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain
embodiments, a dose (e.g. , a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of the quinoline and potentiating agent described herein.
[00188] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose for an adult human whose body weight is approximately 70 kg.
[00189] It will be also appreciated that the pharmaceutical composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. The pharmaceutical compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
[00190] The pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In certain embodiments, the one or more additional therapeutically active agents are different from the compounds and compositions described herein. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
[00191] Exemplary additional therapeutically active agents include, but are not limited to, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Exemplary additional therapeutically active agents also include, but are not limited to, cytotoxic agents. Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
[00192] In anther aspect, the present invention provides a kit for treating or preventing an infectious disease in a subject, wherein the kit comprising: a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject.
[00193] In anther aspect, the present invention provides a kit for preventing biofilm formation in a subject, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject. [00194] In anther aspect, the present invention provides a kit for treating biofilm formation on an object, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical
composition to the object.
[00195] In anther aspect, the present invention provides a kit for eradicating a biofilm, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical composition to the object.
[00196] In anther aspect, the present invention provides a kit comprising: a container comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof; and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit is for treating or preventing an infectious disease in a subject. In certain embodiments, the kit is for preventing biofilm formation in a subject. In certain embodiments, the kit is for preventing biofilm formation on an object. In certain embodiments, the kit is for reducing or eradicating biofilm in a subject. In certain embodiments, the kit is for reducing or eradicating biofilm on an object. In certain embodiments, the instructions are for administrating the compound or pharmaceutical composition in a subject. In certain embodiments, the instructions are for applying the compound or pharmaceutical composition to an object.
[00197] The kits provided may comprise a device, e.g., a vial, ampule, bottle, syringe, and/or dispenser, for administering or applying the pharmaceutical composition as described herein. In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition described herein provided in the first container and the second container are combined to form one unit dosage form.
Method of Treatment
[00198] Infectious diseases are typically caused by microbial pathogens (e.g., viruses, viroids, prions, microorganisms such as bacteria, nematodes such as roundworms and pinworms, arthropods such as ticks, mites, fleas, and lice, fungi such as ringworm, and parasites such as protozoa, multicellular parasites, or tapeworms) into the cells ("host cells") of a subject ("host"). In certain embodiments, the infectious disease is a bacterial infection. In certain embodiments, the infectious disease is a mycobacterial infection. In certain embodiments, the infectious disease is a viral infection. In certain embodiments, the infectious disease is a parasitic infection. In certain embodiments, the infectious disease is a multicellular-parasitic infection. In certain embodiments, the infectious disease is a fungal infection. In certain embodiments, the infectious disease is a protozoan infection.
[00199] In another aspect, the inventive methods for preventing and/or treating an infectious disease comprise administering to a subject in need thereof a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient.
[00200] In yet another aspect, the present invention provides methods for preventing an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00201] In yet another aspect, the present invention provides methods for treating an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00202] In certain embodiments, the infectious disease is responsive to the chelation or sequestration of a metal. In certain embodiments, the metal is a monovalent, divalent, tetravalent, pentavalent, or hexavalent metal. In certain embodiments, the metal is a monovalent metal. In certain embodiments, the metal is a divalent metal. In certain embodiments, the metal is a trivalent metal. In certain embodiments, the metal is aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uranium). In certain embodiments, the metal is iron (e.g. , Fe(II)). In certain embodiments, the metal is zinc (e.g. , Zn (II)). In certain embodiments, the metal is copper (e.g. Cu (II)).
[00203] In certain embodiments, the infectious disease being treated and/or prevented is a bacterial infection. In certain embodiments, the bacterial infection being treated and/or prevented is a chronic bacterial infection. As used herein, a "chronic bacterial infection" is a bacterial infection that is of a long duration or frequent recurrence. For example, a chronic middle ear infection, or otitis media, can occur when the Eustachian tube becomes blocked repeatedly due to allergies, multiple infections, ear trauma, or swelling of the adenoids. The definition of "long duration" will depend upon the particular infection. For example, in the case of a chronic middle ear infection, it may last for weeks to months. Exemplary chronic bacterial infections include, but are not limited to, urinary tract infection (most commonly caused by Escherichia coli and/or Staphylococcus saprophyticus), gastritis (most commonly caused by Helicobacter pylori), respiratory infection (such as those commonly afflicting patents with cystic fibrosis, most commonly caused by Pseudomonas aeuroginosa), cystitis (most commonly caused by Escherichia coli), pyelonephritis (most commonly caused by Proteus species, Escherichia coli and/or Pseudomonas sp), osteomyelitis (most commonly caused by Staphylococcus aureus, but also by Escherichia coli), bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones (can be caused by Proteus mirabilis), bacterial endocarditis, and sinus infection.
[00204] In some embodiments, the bacterial infection is one or more infections selected from the group consisting of urinary tract infection, gastritis, respiratory infection, cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, and sinus infection. In certain embodiments, the infectious diseases is pneumonia, urinary tract infection, complicated intra-abdominal infection, or complicated skin/skin structure infection. In certain embodiments, the infectious diseases is nosocomial pneumonia, community- acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, or melioidosis. In certain embodiments, the bacterial infection is respiratory infection. In certain
embodiments, the bacterial infection is upper respiratory infection. In certain embodiments, the bacterial infection is pneumonia. In certain embodiments, the bacterial infection is bronchitis.
[00205] In some embodiments, the bacterial infection is caused by a Gram positive bacteria. Exemplary Gram positive bacteria include, but are not limited to, Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, and Corynebacterium. In certain embodiments, the Gram positive bacteria is a bacteria of the phylum Firmicutes. In certain embodiments, the bacteria is a member of the phylum
Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection. Exemplary Enterococci bacteria include, but are not limited to, E. avium, E.
durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E.
rqffinosus. In certain embodiments, the Enterococcus infection is an E. faecalis infection. In certain embodiments, the Enterococcus infection is an E. faecium infection. In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus
Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection. Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S.
penttenkoferi, S. piscifermentans, S. psuedointermedius, S. psudolugdensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. warneri, and S. xylosus. In certain embodiments, the Staphylococcus infection is an S. aureus infection. In certain embodiments, the
Staphylococcus infection is an S. epidermis infection.
[00206] In certain embodiments, the bacterial infection is a Gram negative bacteria.
Exemplary Gram negative bacteria include, but are not limited to, Escherchia coli,
Caulobacter crescentus, Pseudomonas, Agrobacterium tumefaciens, Branhamella
catarrhalis, Citrobacter diversus, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhimurium, Neisseria meningitidis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Salmonella enteriditis,
Fusobacterium nucleatum, Veillonella parvula, Bacteroides forsythus, Actinobacillus actinomycetemcomitans, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Helicobacter pylori, Francisella tularensis, Yersinia pestis, Morganella morganii, Edwardsiella tarda, and Haemophilus influenzae. In certain embodiments, the Gram negative bacteria species is Pseudomonas. In certain embodiments, the Gram negative bacteria species is Pseudomonas aeruginosa. In certain embodiments, the Gram negative bacteria species is Acinetobacter baumannii.
[00207] In certain embodiments, the bacterial infection being treated and/or prevented is caused by an organism resistant to one or more antibiotics. For example, in certain embodiments, the bacterium is resistant to penicillin. In certain embodiments, the bacterium is resistant to vancomycin (VR). In certain embodiments, the bacterium is vancomycin- resistant E. faecalis. In certain embodiments, bacterium is vancomycin-resistant E. faecium. In certain embodiments, bacterium is vancomycin-resistant Staphylococcus aureus (VRSA). In certain embodiments, bacterium is vancomycin-resistant Enterococci (VRE). In certain embodiments, the bacterium is a methicillin-resistant (MR) strain. In certain embodiments, the bacterium is methicillin-resistant S. aureus (MRSA). In certain embodiments, the bacterium is methicillin-resistant Staphylococcus epidermidis (MRSE). In certain
embodiments, the bacterium is penicillin-resistant Streptococcus pneumonia. In certain embodiments, the bacterium is quinolone-resistant Staphylococcus aureus (QRSA). In certain embodiments, the bacterium is multi-drug resistant Mycobacterium tuberculosis.
[00208] In some embodiments, the bacterium is susceptible to one or more antibiotics.
In some embodiments, the gram-positive bacterium is susceptible to one or more antibiotics. In some embodiments, the gram- negative bacterium is susceptible to one or more antibiotics. Exemplary antibiotics include, but are not limited to beta-lactams, sulfonamides,
aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides,
oxazolidinones, ansamycins, quinolones, streptogramins, and lipopeptides. In certain embodiments, the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, aminoglycosides, tetracyclines, and quinolones. In certain embodiments, the gram-positive bacterium is susceptible to methicillin. In certain
embodiments, the gram-negative bacterium is susceptible to one or more antibiotics selected from the group consisting of tigecycline, amikacin, ampicillin, and sulbactam.
[00209] As used herein, bacterial susceptibility, also called bacterial sensitivity, refers to inhibition of a bacterial growth by an antimicrobial agent when the recommended dosage is used for the site of infection.
[00210] In another aspect, the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition as described herein.
[00211] In another aspect, the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00212] In certain embodiments, the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a
therapeutically effective amount of the pharmaceutical composition as described herein. In certain embodiments, the biofilms are produced by one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae. In some embodiments, the biofilms are produced by bacteria. In some embodiments, the biofilms are produced by Gram-negative bacteria. In an embodiments, the biofilms are produced by microbial species such as S. epidermidis, E. faecalis, E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, S. aureus, S. viridans, K. oxytoca, S. saprophyticus, L. pneumophila,
Mycobacterium spp., C. freundii, A. hydrophila, F. nucleatum, A. naeslundii, P. stuartii, S. marcescens, or combinations thereof. In some embodiments, the biofilms are produced by Gram-positive bacteria.
[00213] In another aspect, provided herein is a method for inhibiting bacterial cell growth comprising contacting bacteria with the pharmaceutical composition as described herein.
[00214] In another aspect, provided herein is a method for inhibiting bacterial cell growth comprising contacting bacteria with a compound of Formula (C-I), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00215] In another aspect, provided herein is a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with the pharmaceutical composition as described herein.
[00216] In another aspect, provided herein is a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00217] Hypersusceptibility refers to a condition of abnormal susceptibility to poisons, infective agents, or agents that are entirely innocuous in the normal individual.
[00218] In another aspect, provided herein is a method for preventing biofilm formation comprising contacting a subject with the pharmaceutical composition as described herein.
[00219] In another aspect, provided herein is a method for preventing biofilm formation comprising contacting a subject with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00220] In another aspect, provided herein is a method for preventing biofilm formation comprising contacting an object with the pharmaceutical composition as described herein. [00221] In another aspect, provided herein is a method for preventing biofilm formation comprising contacting an object with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00222] In another aspect, provided herein is a method for eradicating biofilm comprising contacting the biofilm with the pharmaceutical composition as described herein.
[00223] In another aspect, provided herein is a method for eradicating biofilm comprising contacting the biofilm with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
[00224] In certain embodiments, the bacterium/a is contacted with the pharmaceutical composition as described herein in vitro. In certain embodiments, the bacterium/a is contacted with the pharmaceutical composition as described herein in vivo. In certain embodiments, the bacterium is subsequently contacted with one or more biocides. In certain embodiments, the biocides are antimicrobials. In certain embodiments, the antimicrobials are antibiotics.
[00225] The compounds of Formulae (I)-(V) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage. Likewise, the compounds of Formulae (C-I) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily dosage of the compositions of the present invention will be decided by an attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient(s) employed; and like factors well known in the medical arts.
[00226] The compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents (e.g., antibiotics, anti-inflammatory agents). In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
[00227] In certain embodiments, the subject administered the quinoline as provided herein or pharmaceutical composition is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is immunodeficient. Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. In certain embodiments, the subject is a patient diagnosed with cystic fibrosis. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is an experimental animal such as a rodent or non-human primate.
[00228] In another aspect, the present invention provides methods to treat or prevent biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of chelating a metal (e.g. , quninoline) or pharmaceutical composition thereof as described herein. In certain embodiments, the provided method treats, cleans, or disinfects a wound by administering the compound or composition as described herein. In certain embodiments, the wounds are chronic wounds, acute wounds, surgical wounds, surgical sites, second and third degree burns, stasis ulcers, tropic lesions, decubitus ulcers, severe cuts, or abrasions.
[00229] In another aspect, the present invention provides methods to treat or prevent biofilm formation comprising contacting an object with an effective amount of a compound capable of chelating a metal (e.g. , quinoline) or the composition as described herein. In certain embodiments, the provided methods inhibit, reduce, or remove biofilms on an object. In certain embodiments, the provided method is to inhibit or remove the biofilm on the surface of the object. In certain embodiments, the surface is a hard, rigid surface. In certain embodiments, the surface is selected from the group consisting of a drainpipe, glaze ceramic, porcelain, glass, metal, wood, chrome, plastic, vinyl, and formica. In certain embodiments, the surface is a soft, flexible surface. In certain embodiments, the surface is selected from the group consisting of shower curtains or liners, upholstery, laundry, and carpeting. In certain embodiments, the surface is a food preparation surface, such as kitchen counters, cutting boards, sinks, stoves, refrigerator surfaces, or on sponges. In certain embodiments, the surface is a bathroom surface such as toilets, sinks, bathtubs, showers, and drains. In certain embodiments, the surface is a medical device surface.
[00230] In some embodiment, the contacting of the compound or composition as described herein with the object is carried out by wiping, sponging, or soaking, or laundering means.
[00231] In some embodiments, the provided method is used to prevent or eradicate biofilm as a dentifrice, a mouthwash, a compound for the treatment of dental caries, acne treatment, cleaning and disinfecting contact lenses, and medically implanted devices that are permanent such as an artificial heart valve or hip joint, and those that are not permanent such as indwelling catheters, pacemakers, surgical pins etc. In some embodiments, the provided method is used to prevent or remove biofilm in situations involving bacterial infection of a host, either human or animal, for example in a topical dressing for burn patients. An example of such a situation would be the infection by P. aeruginosa of superficial wounds such as are found in burn patients or in the lung of a cystic fibrosis patient. In some embodiments, the provided method can be used to control or prevent the development of biofilm in the process of manufacturing integrated circuits, circuit boards or other electronic or microelectronic devices.
Compounds
[00232] In another aspect, the invention also provides quinoline compounds of
Formula (C-I):
Figure imgf000074_0001
or a pharmaceutically acceptable salt thereof,
wherein each of R , R , and R is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, or optionally substituted acyl;
4E
R is hydrogen, halogen, or -N02;
R 5E is hydrogen, halogen, or -N02;
R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group; and provided that R 4E is halogen or N02.
[00233] As generally defined herein, R IE is independently hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted acyl. In certain embodiments, R IE hydrogen. In certain embodiments, R IE is halogen. In certain embodiments, R IE is F. In certain embodiments, R IE is CI. In certain embodiments, R IE is Br. In certain embodiments,
R IE is I. In certain embodiments, R IE is optionally substituted C1-6 alkyl. In certain embodiments, R IE is unsubstituted C1-6 alkyl. In certain embodiments, R IE is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R IE is substituted Ci_6 alkyl. In certain embodiments, R IE is optionally substituted acyl.
[00234] As generally defined herein, R 2E is independently hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted acyl. In certain embodiments, R 2E hydrogen. In certain embodiments, R 2E is halogen. In certain embodiments, R 2E is F. In certain embodiments, R 2E is CI. In certain embodiments, R 2E is Br. In certain embodiments,
R 2E is I. In certain embodiments, R 2E is optionally substituted C1-6 alkyl. In certain embodiments, R 2E is unsubstituted C1-6 alkyl. In certain embodiments, R 2E is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R 2E is substituted Ci_6 alkyl. In certain embodiments, R 2E is optionally substituted acyl.
[00235] In certain embodiments, R 2E is of the Formula (iii)
Figure imgf000075_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORA, or -N(RB)2;
RA is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
[00236] As generally defined herein, R 8E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR , or -N(R )2. In certain embodiments, R is optionally substituted alkyl. In certain embodiments, R 8E is optionally substituted C1-6 alkyl. In certain embodiments, R 8E is unsubstituted C1-6 alkyl. In certain embodiments, R 8E is methyl, ethyl, n- propyl, or isopropyl. In certain embodiments, R 8E is optionally substituted carbocyclyl. In certain embodiments, R 8E is optionally substituted cyclohexyl. In certain embodiments, R 8E is optionally substituted aryl. In certain embodiments, R 8E is optionally substituted phenyl. In certain embodiments, R 8E is optionally substituted heterocyclyl. In certain embodiments, R 8E is optionally substituted heteroaryl. In certain embodiments, R 8E is optionally substituted monocyclic heteroaryl. In certain embodiments, R 8E is optionally substituted 5-membered heteroaryl. In certain embodiments, R 8E is optionally substituted furanyl. In certain embodiments, R 8E is optionally substituted 2-furanyl or 3-furanyl.
[00237] As generally defined herein, R 3E is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, or optionally substituted acyl. In certain embodiments, R 3E is hydrogen. In certain embodiments, R 3E is halogen. In certain embodiments, R 3E is F. In certain embodiments, R 3E is CI. In certain embodiments, R 3E is Br. In certain embodiments,
R 3E is I. In certain embodiments, R 3E is optionally substituted Ci_6 alkyl. In certain
embodiments, R 3E is unsubstituted Ci_6 alkyl. In certain embodiments, R 3E is methyl, ethyl, n- propyl, or isopropyl. In certain embodiments, R 3E is substituted C1-6 alkyl. In certain embodiments, R 3E is optionally substituted acyl.
[00238] As generally defined herein, R 4E is hydrogen, halogen, or -N02. In certain embodiments, R 4E is hydrogen. In certain embodiments, R 4E is halogen. In certain
embodiments, R 4E is F. In certain embodiments, R 4E is CI. In certain embodiments, R 4E is Br.
In certain embodiments, R 4E is I. In certain embodiments, R 4E is N02.
[00239] As generally defined herein, R 5E is hydrogen, halogen, or -N02. In certain embodiments, R 5E is hydrogen. In certain embodiments, R 5E is halogen. In certain
embodiments, R 5E is F. In certain embodiments, R 5E is CI. In certain embodiments, R 5E is Br.
In certain embodiments, R 5E is I. In certain embodiments, R 5E is N02.
[00240] As generally defined herein, R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R 6E is hydrogen. In certain embodiments, R is optionally substituted acyl. In certain embodiments, R is an oxygen protecting group.
In certain embodiments, R 6E is Boc. In certain embodiments, R 6E is of the Formula (iv):
0
¾ (iv),
wherein
R 7E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
[00241] In certain embodiments, R is optionally substituted alkyl. In certain embodiments, R 7E is optionally substituted Ci_6 alkyl. In certain embodiments, R 7E is unsubstituted C1-6 alkyl. In certain embodiments, R 7E is methyl, ethyl, n-propyl, or isopropyl.
In certain embodiments, R 7E is substituted C1-6 alkyl. In certain embodiments, R 7E is optionally substituted carbocyclyl-alkyl. In certain embodiments, R 7E is optionally substituted
7E
cyclopentyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-(CH2)i_5-
7E
. In certain embodiments, R is unsubstituted cyclopentyl-(CH2)i-5-. In certain embodiments,
R 7E is optionally substituted aryl. In certain embodiments, R 7E is optionally substituted phenyl.
me embodiments, R 7E is optionally substituted phenyl of the formula
Figure imgf000077_0001
, wherein e is 0, 1, 2, 3, 4, or 5; R is independently selected from the group consisting of hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 1 and R is optionally substituted alkyl or optionally substituted alkoxy. In certain embodiments, e is 1 and R is one of the
formulae:
Figure imgf000077_0002
. In certain embodiments, e is 2 or
Figure imgf000078_0001
. In certain embodiments e is 3 and R7E is one of the formulae:
Figure imgf000078_0002
or . In certain embodiments, e is 5 and R is of the formula
Figure imgf000078_0003
In certain embodiments, R is optionally substituted alkyl. In certain embodiments, RE is nts, R is one of the
following formulae:
Figure imgf000078_0004
[00243] In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments,
R is optionally substituted 5-membered heteroaryl. In certain embodiments, R 7/EE i ·s optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3 -furanyl.
[00244] In certain embodiments, a provided compound is any compound in Table 1. In certain embodiments, a provided compound is any one of the compounds shown in Table 1, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof (e.g., compounds shown in Table 1, and pharmaceutically acceptable salts thereof).
EXAMPLES
Chemical Synthesis
Compound 30
Figure imgf000079_0001
[00245] 3-Hydroxy-2-nitrobenzaldehyde (28). To a stirring solution of 3- hydroxybenzaldehyde 23 (618 mg, 5.0 mmol) in dichloromethane (10 mL) was added tetrabutylammoniumhydrogen sulfate (85.0 mg, 0.25 mmol) and isopropyl nitrate (1.27 mL, 12.5 mmol). Concentrated sulfuric acid (610 μί) was added dropwise and the resulting reaction mixture was allowed to stir at room temperature for 15 minutes. The reaction contents were then transferred to a separatory funnel containing 50 mL of an aqueous saturated sodium bicarbonate solution. Dichloromethane was then used to extract the crude product. The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was adsorbed onto silica gel and purified via flash column chromatography eluting with 99: 1 to 4: 1 hexanes:ethyl acetate to give isomer 30 (R = 0.44 in 3: 1 hexanes:ethyl acetate) as a yellow solid (201 mg, 24% yield) followed by the desired product 28 (R/= 0.19 in 3: 1 hexanes:ethyl acetate) as a pale yellow solid (411 mg, 47% yield). This is a known procedure (D. A. Learmonth (Portela & C.A., S.A., Port.), GB- 2377934, 2003). We were able to obtain 28 (CAS number: 42123-33-1) in 63% yield during the course of these investigations. Characterization Data for Compound 28: 1H NMR (400 MHz, CDC13): δ 10.40 (s, 1H), 10.30 (s, 1H), 7.67 (ddd, J = 8.3, 7.4, 0.7 Hz, 1H), 7.37 (dd, = 8.3, 1.4 Hz, 1H), 7.31 (dd, J = 7.4, 1.4 Hz, 1H). HRMS (DART): calc. for C7H9N204
[M+NH4]+: 185.0557, found: 185.0559. MP: 155-158 °C, lit. 157 °C (W. S. Saari, S. W. King, J. Med. Chem. 1974, 17, 1086-1090). Characterization Data for 30: 1H NMR (400 MHz, CDCI3): δ 10.58 (s, 1H), 10.06 (d, J = 0.6 Hz, 1H), 8.28 (d, = 8.7 Hz, 1H), 7.66 (d, = 1.7 Hz, 1H), 7.51 (dd, = 8.7, 1.7 Hz, 1H). Spectral values for 30 identical to previously reported 1H NMR data (A. Tsoukala, L. Liguori, G. Occhipinti, H.R. Bjorsvik, Tet. Lett. 2009, 50, 831-833). MP: 129-131 °C, lit. 127°C (J. Cologne, F. Pierre, Bull. Soc. Chim. Fr. 1964, 12, 3090-3096).
Compounds 25-27 (Friedlander S nthesis)
Figure imgf000080_0001
[00246] 2-Amino-3-hydroxybenzaldehyde (24). Iron powder (895 mg, 16 mmol) was added to a stirring solution of 3-hydroxy-2-nitrobenzaldehyde 28 (268 mg, 1.60 mmol) dissolved in 4: 1 mixture of ethanokwater (6 mL). Concentrated hydrochloric acid (14
Figure imgf000080_0002
0.16 mmol) was added to the reaction mixture which was heated to reflux for 5 hours until complete (determined by TLC analysis). After the completion of the reaction, the reaction was cooled and the resulting suspension was passed through a short plug of celite eluting with ethanol. The resulting solution was concentrated in vacuo to afford pure 24 (186.6 mg, 85% yield). This procedure has been previously described [27, 28]. Characterization Data or 24: 1H NMR (400 MHz, CDCI3): δ 9.88 (s, 1H), 7.14 (dd, = 7.8, 1.3 Hz, 1H), 6.87 (dd, = 7.8, 1.3 Hz, 1H), 6.61 (dd, = 7.8 Hz, 7.8 Hz, 1H), 6.29 (br. s, 2H). 1H NMR (400 MHz, i¾-MeOD): δ 9.80 (s, 1H), 7.05 (dd, = 7.9, 1.3 Hz, 1H), 6.84 (dd, = 7.6, 1.3 Hz, 1H), 6.56 (dd, = 7.9, 7.6 Hz, 1H). 13C NMR (100 MHz, <¾-MeOD): δ 195.6, 145.6, 141.8, 126.9, 119.9, 118.8, 116.3. HRMS (DART): calc. for C7H8N02 [M+H]+: 138.0550, found:
138.0546. MP: 124-126 °C.
Figure imgf000080_0003
[00247] To a stirring solution of 2-amino-3-hydroxybenzaldehyde 24 (137 mg, 1.0 mmol) in water (6 mL) was added the corresponding diketone/B-ketoester (1.2 mmol). The resulting mixture was then allowed to stir at 70 °C for 5 hours until complete. After that time, the reaction was then allowed to cool and the contents were then transferred to a separatory funnel containing a saturated aqueous solution of sodium bicarbonate. The solution was then extracted with ethyl acetate three times. The organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified via flash column chromatography using eluting with 95:5 to 4: 1 hexanes:ethyl acetate to give respective 8-hydroxyquinolines 25-27 (26-65% yield). We used a modified Friedlander quinoline synthesis procedure previously reported by Shen and coworkers (Q. Shen, L. Wang, J. Yu, M. Liu, J. Qiu, L. Fang, F. Guo, J. Tang, Synthesis 2012, 44, 389-392).
Figure imgf000081_0001
25
[00248] Compound 25 was isolated as a white solid (81.0 mg, 58%). 1H NMR (400
MHz, CDCI3): δ 8.48 (s, 1H), 7.45 (t, 7 = 7.9 Hz, 1H), 7.36 (dd, 7 = 8.3, 1.2 Hz, 1H), 7.23 (dd, 7 = 7.5, 0.9 Hz, 1H), 2.90 (s, 3H), 2.72 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 200.0, 156.0, 151.8, 138.5, 138.0, 132.0, 128.0, 126.0, 118.6, 112.3, 29.5, 25.7 HRMS (DART): calc. for Ci2Hi2N02 [M+H]+: 202.0863, found: 202.0872. MP: 111-113 °C.
Figure imgf000081_0002
26
[00249] Compound 26 was isolated as a clear oil (63.0 mg, 26%). 1H NMR (400 MHz,
CDCl3): 5 8.10 (s, 1H), 7.87 - 7.81 (m, 2H), 7.64 (ddt, 7 = 7.9, 6.9, 1.3 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.44 (dd, 7 = 8.3, 7.6 Hz, 1H), 7.29 (dd, 7 = 8.3, 1.2 Hz, 1H), 7.23 (dd, 7 = 7.6, 1.2 Hz, 1H), 2.73 (s, 3H). 13C NMR (100 MHz, CDC13): δ 196.8, 155.0, 151.8, 137.9, 137.3, 137.0, 133.9, 133.0, 130.3, 128.9, 127.9, 125.6, 118.3, 111.7, 24.1. HRMS (DART): calc. for Ci7Hi4N02 [M+H]+: 264.1019, found: 264.1026.
Figure imgf000081_0003
27
[00250] Compound 27 was isolated as a white solid (154.4 mg, 65%). 1H NMR (400
MHz, CDC13): δ 8.65 (s, 1H), 7.39 (dd, 7 = 8.3, 7.5 Hz, 1H), 7.29 (dd, 7 = 8.3, 1.3 Hz, 1H), 7.19 (dd, 7 = 7.5, 1.3 Hz, 1H), 4.42 (q, 7 = 7.1 Hz, 2H), 2.93 (s, 3H), 1.44 (t, 7 = 7.2 Hz, 3H) 13C NMR (100 MHz, CDC13): δ 166.4, 156.7, 151.6, 140.0, 138.3, 127.7, 126.0, 124.7, 118.6, 112.1, 61.6, 25.6, 14.5. HRMS (DART): calc. for C13H13NO3 [M+H]+: 232.0968, found: 232.0976. MP: 61-63 °C.
Compounds 8-11
Figure imgf000082_0001
X = Br; I
[00251] 8-Hydroxyquinoline (155 mg, 0.67 mmol) was dissolved in toluene (15 niL) before N-bromosuccinimide (240 mg, 1.34 mmol) was added and allowed to stir at room temperature for two hours until reaction was complete (monitored by TLC). At this time, the reaction was concentrated and adsorbed onto silica gel (via dissolving the crude reaction contents and silica gel in dichloromethane, then concentrating via rotavap) and purified via column chromatography using dichloromethane to elute pure 8-hydroxy-5,7-dihaloquinolines 8-11 (62-94% yield). lodination reactions were accomplished by using 2.0-2.2 equivalents of N-iodo succinimide .
Figure imgf000082_0002
8
[00252] Compound 8 was isolated as a white solid (120.3 mg, 94%). 1H NMR (400
MHz, CDCI3): δ 8.66 (s, 1H), 7.84 (s, 1H), 2.91 (s, 3H), 2.76 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 199.4, 158.1, 149.2, 138.0, 137.9, 133.9, 132.8, 124.3, 110.6, 106.3, 29.5, 25.4. HRMS (DART): calc. for Ci2HioBr2N02 [M+H]+: 357.9073, found: 357.9090. MP: 183- 185 °C.
Figure imgf000082_0003
9
[00253] Compound 9 was isolated as an off-white solid (32.8 mg, 62%). 1H NMR (400
MHz, CDCI3): δ 8.35 (s, 1H), 7.89 (s, 1H), 7.84 (m, 2H), 7.68 (ddt, J = 7.9, 7.0, 1.3 Hz, 1H), 7.53 (m, 2H), 2.74 (s, 3H). 13C NMR (100 MHz, CDC13): δ 195.9, 157.0, 149.3, 138.1, 136.8, 136.4, 134.4, 134.3, 134.0, 130.4, 129.1, 124.2, 110.6, 105.6, 23.9. HRMS (DART): calc. for Ci7Hi2Br2N02 [M+H]+: 419.9229, found: 419.9234. MP: 190-192 °C.
Figure imgf000083_0001
10
[00254] Compound 10 was isolated as a white solid (232.7 mg, 90%). 1H NMR (400
MHz, CDC13): δ 8.84 (s, 1H), 7.80 (s, 1H), 4.47 (q, = 7.1 Hz, 2H), 2.97 (s, 3H), 1.47 (t, = 7.1 Hz, 3H). 13C NMR (100 MHz, CDC13): δ 165.8 158.8, 149.1, 139.6, 138.3, 133.8, 126.0, 124.4, 110.7, 106.2, 62.1, 25.4, 14.5. HRMS (DART): calc. for Ci3Hi2Br2N03 [M+H]+: 387.9178, found: 387.9165. MP: 148-150 °C.
Figure imgf000083_0002
11
[00255] Compound 11 was isolated as a pale yellow solid (38.6 mg, 92%). 1H NMR
(400 MHz, CDC13): δ 8.74 (s, 1H), 8.26 (s, 1H), 4.47 (q, = 7.1 Hz, 2H), 2.98 (s, 3H), 1.48 (t, = 7.1 Hz, 3H). 13C NMR (100 MHz, CDC13): δ 165.8, 158.8, 153.4, 145.2, 144.1, 137.4, 127.6, 126.7, 85.2, 79.8, 62.1, 25.2, 14.5. HRMS (DART): calc. for Ci3Hi2I2N03 [M+H]+: 483.8901, found: 483.8911. MP: 180-182 °C.
Figure imgf000083_0003
29 13
[00256] 8-Hydroxy-7-iodo-2,3,4-trimethylquinoline (13). To a stirring solution of 8- hydroxyquinoline 29 (50.8 mg, 0.22 mmol) in anhydrous dichloromethane (4 mL) was added N-iodosuccinimide (61.1 mg, 0.27 mmol). The resulting reaction mixture was allowed to stir at room temperature for two hours. Upon completion of the reaction, the mixture was concentrated, adsorbed onto silica gel and purified via column chromatography using dichloromethane to elute 13 as a pale yellow solid (74.4 mg, 88% yield). Note: We previously reported the synthesis of quinoline 29 (Y. Abouelhassan, A. T. Garrison, G. M. Burch, W. Wong, V. M. Norwood IV, R. W. Huigens III, Bioorg. Med. Chem. Lett. 2014, 24, 5076-5080). 1H NMR (400 MHz, CDC13): δ 7.79 (br. s, 1H), 7.60 (d, = 9.0 Hz, 1H), 7.10 (d, = 9.0 Hz, 1H), 2.62 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 157.0, 152.7, 141.6, 135.1, 134.5, 129.3, 126.8, 115.7, 74.7, 24.7, 16.0, 14.8. HRMS
(DART): calc. for C12H13INO [M+H]+: 314.0036, found: 314.0051. MP: 109-111 °C.
Figure imgf000084_0001
13 15
[00257] 5-Bromo-8-hydroxy-7-iodo-2,3,4-trimethylquinoline (15). To a stirring solution of 8-hydroxyquinoline 13 (23.4 mg, 0.075 mmol) in anhydrous dichloromethane (4 mL) was added N-bromosuccinimide (14.6 mg, 0.082 mmol). The resulting reaction mixture was allowed to stir at room temperature for two hours. Following the completion of the reaction, the solvent was removed in vacuo, adsorbed onto silica gel and purified via column chromatography using dichloromethane to elute 15 as a pale yellow solid (15.4 mg, 53% yield). 1H NMR (400 MHz, CDC13): δ 8.00 (s, 1H), 2.93 (s, 3H), 2.68 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, CDC13): δ 157.3, 153.0, 143.5, 140.3, 136.1, 131.7, 125.9, 107.2, 73.6, 24.8, 19.7, 16.8. HRMS (DART): calc. for Ci2Hi2BrINO [M+H]+: 391.9141, found:
391.9139. MP: 123-127 °C.
Figure imgf000084_0002
Nitroxoline (17) 16
[00258] 7-Bromo-8-hydroxy-4-nitroquinoline (16). N-bromosuccinimide (492 mg,
2.76 mmol) was added to a stirring solution of nitroxoline 17 (500 mg, 2.63 mmol) in tetrahydrofuran (16 mL), followed by the addition of a catalytic amount of concentrated sulfuric acid (15 The resulting mixture was then allowed to stir for 90 minutes at room temperature. At that time, the reaction mixture was poured onto 50 mL of water and the resulting suspension was filtered. The solid was then collected and dried under vacuum to afford 16 as a bright orange solid (457 mg, 65% yield). Note: This protocol was previously described by Boger and coworkers. The spectral data and melting point that we obtained for this compound are in complete agreement with data previously reported (D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5782-5789). 1H NMR (400 MHz, d6- DMSO): δ 9.32 (d, J = 8.8 Hz, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.73 (s, 1H), 7.98 (dd, / = 8.8, 4.4 Hz, 1H). 13C NMR (100 MHz, d6-DMSO): δ 159.9, 147.3, 135.7, 135.3, 132.4, 131.5, 125.5, 122.8, 104.5. MP: 198-200 °C, lit. 199 °C (D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5782-5789).
Figure imgf000085_0001
[00259] 5,7-Dibromoquinolin-8-yl isobutyrate (19). To a stirring solution of 4 (77.0 mg, 0.10 mmol), triethylamine (143 μί, 0.40 mmol) and a catalytic amount of 4- dimethlyaminopyridine in dichloromethane (3 mL) was added isobutyryl chloride (28 μί) dropwise at room temperature. The reaction was then allowed to stir for one hour before being quenched with an aqueous solution of saturated sodium bicarbonate. The resulting mixture was then transferred to a separatory funnel and ethyl acetate was added to extract. The organic layer was sequentially washed with sodium bicarbonate and brine before being collected, then dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash column chromatography eluting with 99: 1 to 4: 1 hexanes:ethyl acetate to afford 19 as a colorless residue (63.0 mg, 65% yield). 1H NMR (400 MHz, CDC13): δ 8.91 (dd, / = 4.2, 1.6 Hz, 1H), 8.48 (dd, / = 8.6, 1.6 Hz, 1H), 8.03 (s, 1H), 7.54 (dd, = 8.6, 4.2 Hz, 1H), 3.11 (sept, = 7.0 Hz, 1H), 1.48 (d, = 7.0 Hz, 6H). 13C NMR (100 MHz, CDCI3): δ 174.5, 151.9, 145.7, 142.7, 135.9, 133.2, 127.9, 123.0, 119.2, 116.9, 34.4, 19.3. HRMS (DART): calc. for Ci3Hi2Br2N02 [M+H]+: 371.9229, found: 371.9246.
Biological Evaluation
Materials and Methods
[00260] All synthetic reactions were carried out under an inert atmosphere of argon unless otherwise specified. All reagents for chemical synthesis were purchased from commercial sources and used without further purification. Compounds 2, 3, 4, 5, 6, 7, 17, 18, and gallic acid were purchased at > 95% purity and were used in our biological investigations without further purification. Analytical thin layer chromatography (TLC) was performed using 250 μιη Silica Gel 60 F254 pre-coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230-400 Mesh 60A Silica Gel from Sorbent
Technologies.
[00261] NMR experiments were recorded using broadband probes on a Varian
Mercury-Plus-400 spectrometer via VNMR-J software (400 MHz for 1H and 100 MHz for
13 C). All spectra are presented using MestReNova 8.1 (Mnova) software and are displayed without the use of the signal suppression function. Spectra were obtained in the following solvents (reference peaks also included for 1H and 13C NMRs): CDC13 (1H NMR: 7.26 ppm; 13C NMR: 77.23 ppm), i¾-DMSO (1H NMR: 2.50 ppm; 13C NMR: 39.52 ppm) and i¾-MeOD (1H NMR: 3.31 ppm; 13C NMR: 49.00 ppm). All NMR experiments were performed at room temperature. Chemical shift values (δ) are reported in parts per million (ppm) for all 1H
NMR and 13 C NMR spectra. 1 H NMR multiplicities are reported as: s = singlet, br. s = broad singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septet, m = multiplet. High- resolution mass spectra were obtained for all new compounds from the Chemistry
Department at the University of Florida.
[00262] All compounds were stored as DMSO stocks at room temperature in the absence of light for several months at a time without observing any loss in biological activity. To ensure compound integrity of our DMSO stock solutions, we did not subject DMSO stocks of our test compounds to freeze-thaw cycles.
Potentiation of Antibacterial Activity Assay (determined by MIC comparison):
[00263] The minimum inhibitory concentration (MIC) for each test compound was determined by the broth microdilution method as recommended by the Clinical and
Laboratory Standards Institute (CLSI) (Clinical and Laboratory Standards Institute. 2009. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 8th edition (M7-M8), Clinical and Laboratory Standard, Wayne, PA, 2009). In a 96- well plate, eleven two-fold serial dilutions of each compound were made in a final volume of 100 μΐ^ in Luria Broth media. Half of the 96-well plate contained media treated with phytochemical potentiating agent (at sub-inhibitory concentrations). Each well was inoculated with ~105 bacterial cells at the initial time of incubation, prepared from a fresh log phase culture (ODeoo of 0.5 to 1.0 depending on bacterial strain). 100 mM stocks of each phytochemical potentiating agent (dissolved in water for Tiron and in DMSO for Gallic Acid and Caffeic Acid) was prepared and then added at non-growth inhibiting concentrations (1 niM and 250 μΜ were used during these studies). The plates were incubated for 16-18 hours at 37° C and the MIC was then defined as the lowest concentration of compound that prevented bacterial growth (MIC values were determined by spectrophotometric readings at Οϋόοο)· DMSO served as our vehicle and negative control in each microdilution MIC assay (serially diluted at the top concentration of 1% v/v). Bacterial strains used: Staphylococcus aureus (ATCC strains: 29213, BAA-1707; clinical isolates MRSA-1, MRSA-2, SA-156), Staphylococcus epidermidis (ATCC 12228; clinical isolate MRSE-1), Acinetobacter baumannii (ATCC strains: 19606, BAA-1794), Klebsiella pneumonia (ATCC 13883) and Pseudomonas aeruginosa (PAOl) (Figure 4). S. epidermidis clinical isolate (methicillin- resistant Staphylococcus epidermidis or "MRSE-1") was slow growing under standard assay conditions, so Mueller Hinton Broth was used as the media in potentiation assays during these investigations. All potentiation data was obtained from 2 to 4 independent assays described above.
[00264] The growth-inhibitory effect of quinoline compounds-phytochemical combinations were tested against S. aureus ATCC 29213. Gallic acid showed the dramatic potentiation of exemplified quinoline compounds growth inhibition against S. aureus 29213 (up to 11,800-fold potentiation; Table 2) while caffeic acid and tiron demonstrated good potentiation activities of exemplified quinoline compounds (Figures 14 and 15).
Table 2. Summary of Gallic Acid (GA) potentiation activities of exemplified quinoline compounds and control compounds against Staphylococcus aureus strain ATCC 29213
S. aureus Quinoline compound MIC [μΜ] MIC with GA [μΜ]3 Potentiation
/GA
29213 1 0.59b 0.00005 1 1 ,800
29213 2 12.5 0.39 32
29213 3 25 2.35b 1 1
29213 4 12.5 0.59b 24
29213 5 12.5 0.1 125
29213 6 12.5 0.39 32
29213 7 1 .56 0.075b 21
29213 8 1 .17b 0.39 3
29213 9 0.59b 0.075b 8
29213 10 0.39 0.038b 10
29213 1 1 0.78 0.009b 86
29213 12 6.25 0.075b 83 29213 13 25 0.39 64
29213 14 9.38b 0.1 94
29213 1 5 12.5 0.1 125
29213 1 6 6.25 2.35b 3
29213 1 7 25 3.13 8
29213 1 8 9.38b 50 - 6
29213 1 9 1 8.8b 0.39 48
29213 20 12.5 0.2 63
29213 21 0.59b 0.001 6b 369
29213 22 0.78 0.0063 124
29213 GA >5,000 -- --
Notes: [a] GA concentration for potentiation assays was 1 mM (<l/5 MIC), [b] Midpoint MIC value for observed 2-fold range in potentiation assays.
Table 3. Gallic Acid- exemplified quinoline compounds potentiation studies against MRSA clinical isolates and other pathogenic bacteria.
Strain Quinoline MIC MIC with GA Potentiation
MRSA BAA- 1707a 1 0.78 0.038c 21
MRSA BAA- 1707 4 12.5 0.2 63
MRSA BAA- 1707 5 12.5 0.1 125
MRSA-la 1 0.78 0.05 16
MRSA-1 4 12.5 0.2 63
MRSA-1 5 9.38c 0.038c 247
MRSA-2b 1 0.78 0.39 2
MRSA-2 4 12.5 0.78 16
MRSA-2 5 12.5 0.39 32
MRSA SA-156a 1 0.39 0.00039 1,000
MRSA SA-156 4 12.5 0.15c 83
MRSA SA-156 5 12.5 0.1 125
S. epi. MRSE-lb 1 3.13 0.39 8
S. epi. MRSE-1 4 12.5 1.17c 11
S. epi. MRSE-1 5 12.5 0.59c 21
A. baumanii BAA- 1 > 100* 9.38c 11
1794a
A. baumanii BAA- 4 12.5 0.3C 42 1794
A. baumanii BAA- 5 > 100* 1.56 > 64
1794
K. pneumoniae 1 > 100 6.25 > 16
13883a
K. pneumoniae 13883 4 > 100* 1.56 > 64
K. pneumoniae 13883 5 >100 18.8C > 5
Notes: [a] GA test concentration 1,000 μΜ. [b] GA test concentration 250 μΜ. [c] Midpoint MIC value for observed 2-fold range in potentiation assays.
[00265] Further evaluated are gallic acid combinations with conventional antibacterial agents including: ciprofloxacin (targets DNA gyrase/topoisomerase IV; inhibits DNA synthesis), methicillin (targets transpeptidase; inhibits cell wall synthesis), erythromycin (targets 50S subunit of ribosome; inhibits protein synthesis), tobramycin (targets 30S and 50S subunits of ribosome; inhibits protein synthesis) and vancomycin (targets pentapeptides; inhibits cell wall synthesis). None of these antibacterial agents were potentiated by GA. This result points to a unique antibacterial mechanism for quinoline compounds that differs from conventional antibiotics.
[00266] After identifying the uniquely potent antibacterial combination of 1 and GA, we were curious to know if we could potentiate biofilm eradication (complete demolition of bacterial cells within a biofilm) against a methicillin-resistant S. aureus clinical isolate (MRSA-2) with this antibacterial combination since we have previously described potent staphylococcal biofilm-clearing activities of 1 in crystal violet reporter assays. We recently reported that vancomycin is unable to eradicate clinical isolate MRSA-2 biofilms at high concentrations (up to 2 mM) despite possessing potent antibacterial activity against MRSA-2 planktonic cells (MIC 0.78 μΜ) (A. T. Garrison, F. Bai, Y. Abouelhassan, N. G. Paciaroni, S. Jin, R. W. Huigens III, RSC Advances, 2015, 5, 1120-1124). This is illustrative of the drug- resistant phenotype displayed by bacterial biofilms (surface-attached bacterial communities) which are known to occur in the majority of bacterial infections. When tested incombination, gallic acid potentiates the biofilm eradication activity of 1 against MRSA-2 biofilms 4-fold (MBEC of 1 is 250 μΜ when tested alone and 62.5 μΜ when tested with gallic acid in biofilm eradication assays; Figure 3B).
[00267] The effectiveness of this quinoline compounds -Gallic Acid combination against a broad spectrum of human pathogens were evaluated, including: Staphylococcus epidermidis, Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. A panel of 14 quinoline compounds were tested against the MRSA clinical isolates. It was found that quinoline compounds have moderate antibacterial activity against gram-negative pathogens (Y. Abouelhassan, A. T. Garrison, G. M. Burch, W. Wong, V. M. Norwood IV, R. W. Huigens III, Bioorg. Med. Chem. Lett. 2014, 24, 5076-5080).
[00268] Further evaluated are quinoline compounds -Gallic Acid combinations against
S. epidermidis. Methicillin-susceptible ATCC 12228 strain was used in addition to a methicillin-resistant S. epidermidis (MRSE-1) clinical isolate. GA was found to have some antibacterial activities against these strains (MICs 469 and 625 μΜ, respectively). About 250 μΜ of GA was used in these potentiation assays (-1/2 MIC). The overall potentiation of exemplified quinoline compounds by GA was less dramatic against S. epidermidis (4- to 63- fold potentiation) compared to S. aureus, but 9 of 13 exemplified quinoline compounds (69%) tested in the panel were potentiated against both S. epidermidis strains.
[00269] Further evaluated are GA combinations against the gram-negative pathogen A. baumannii, including both susceptible (ATCC 19606) and multidrug-resistant (ATCC strain BAA- 1794) strains. ATCC reports that BAA- 1794 is resistant to 30 of 34 antibiotics tested (susceptible only to tigecycline, amikacin and ampicillin/sulbactam in their panel) which include β-lactam, aminoglycoside, tetracycline and fluoroquinolone drugs. Quinoline antibacterial agent nitroxoline 17 shows good antibacterial potency (MIC 6.25 μΜ), but is not potentiated with GA. Most exemplified quinoline compounds demonstrate little or no antibacterial activity (MICs 25 to >100 μΜ) as single antibacterial agents against A.
baumannii; however, against MDR strain BAA- 1794, the quinoline compounds-GA combination demonstrates good antibacterial activity for select exemplified quinoline compounds, including: 1 (MIC: >100 μΜ; MIC + GA: 9.38 μΜ), 4 (MIC: 25 μΜ; MIC + GA: 0.3 μΜ) and 5 (MIC: >100 μΜ; MIC + GA: 1.56 μΜ). Ester quinoline compounds 20 and 21 also demonstrated GA potentiation similar to their free hydroxyl counterparts (20 with 4; 21 with 1), most likely through a prodrug esterase cleavage mechanism. These esters did provide slight increases in antibacterial potencies (with and without GA) compared to their corresponding hydroxyl quinoline compounds (1 and 4).
[00270] A panel of exemplified quinoline compounds in combination with GA were tested against the gram- negative pathogens P. aeruginosa (PAOl) and K. pneumoniae (ATCC 13883). No potentiation of antibacterial activity was observed with the exemplified quinoline compounds -GA combination against PAOl (MICs for all exemplified quinoline compounds > 100 μΜ with and without GA). GA potentiation of some quinoline compounds were found against K. pneumoniae such as 1, 4, 5, 17 (nitroxoline), 20 and 21. Gallic Acid Potentiation of Halogenated Quinoline 1 in MRSA-2 Biofilm Eradication Assay:
[00271] A single colony grown on LB agar solid medium was amplified in 2 milliliters of tryptic soy broth (TSB) medium with 0.5% glucose to an OD6oo ~ 1-0. The bacterial suspension was then diluted to -lxlO6 CFUmL"1 in TSB with 0.5% glucose. Sterile 96-well flat-bottomed polystyrene plates (0.1% gelatin coated overnight) were then filled with 100 μΐ^ of this bacterial suspension. The microtiter plates were then covered and incubated for 24 hours at 37 °C. Following this, the contents of the wells were discarded and washed with water three times (wells were rinsed by submerging the entire plates in a tub of cold, running tap water). Then serial, two-fold dilutions of test compound in 100 μΐ^ TSB 0.5% glucose were delivered into each well at concentrations ranging from 2 to 2,000 μΜ (DMSO did not exceed 2% v/v in these assays). Gallic acid (i.e., potentiating agent) was added at a final concentration of 1 mM. The plates were then covered with a lid, wrapped in saran wrap and incubated with test compounds for 24 hours at 37 °C. After this time, the contents within each well were removed and the plates were gently washed with water three times as before. The remaining biofilms were treated with TSB with 0.5 % glucose (100 μί) and allowed to incubate for 24 hours at 37 °C. Following this final incubation, biofilm eradication was determined accordingly (microtiter wells that were turbid resulted from live biofilm/bacterial growth while microtiter wells that had no turbidity resulted from completely eradicated biofilms). Minimum Biofilm Eradication Concentration (MBEC) values were determined as the lowest concentration of a test compound that resulted in complete biofilm eradication.
Metal(II) Cation Potentiation Antibacterial Assay against S. aureus 29213:
[00272] 8-Hydroxyquinolines contain a metal binding motif which includes the phenolic oxygen and heterocyclic nitrogen atom of the quinoline ring which can chelate various metal(II) cations (V. Prachayasittikul, S. Prachayasittikul, S. Ruchirawat, V.
Prachayasittikul, Drug Des. Devel. Ther., 2013, 7, 1157-1178). It has been proposed that 8- hydroxyquinolines elicit their antibacterial properties through mechanisms that involve metal cation binding [17-20]. The quinoline compounds library in potentiation assays with Zn2+, Fe2+ and Cu2+ cations against S. aureus 29213 were evaluated to determine if metal(II) cations were involved in the antibacterial mechanism of quinoline compounds.
[00273] Zinc(II)-, iron(II)- and copper(II)-cations were added in potentiation assays in an analogous fashion to potentiating agents (i.e., gallic acid) in the potentiation protocol described above. Metal(II)-cations used during these studies included: ZnCl2, (NH4)2Fe(S04)2-6H20 and CuS04. Zinc(II) chloride (at 100 μΜ; <l/7 MIC) was found to potentiate the antibacterial activities of quinoline compounds 4 and 5 by 21- and 83-fold, respectively. The presence of 100 μΜ zinc(II) chloride potentiates the antibacterial activities of 90% (18/20) of the quinoline library (4- to 83-fold) against S. aureus 29213. Ammonium iron(II) sulfate (at 100 μΜ, <1/10 MIC) had the opposite effect by diminishing antibacterial activities of 18 of 20 (90%) quinoline compounds. Finally, the quinoline library was treated with copper(II) sulfate (at 100 μΜ; <1/10 MIC) and observed both positive potentiation (7 of 20; 35%) and suppression (6 of 20; 30%) of antibacterial activities with different exemplified quinoline compounds. 8-Hydroxyquinoline 18 and nitroxoline 17 do not possess any halogen atoms and were not potentiated by ZnCl2, but did follow iron(II) and copper(II) potentiation trends similar to the exemplified quinoline compounds.
[00274] Conventional antibiotics with diverse antibacterial targets were also evaluated in combination with metal(II) cations and showed no potentiation or suppression of antibacterial activities. Known metal binding compounds, EDTA and TPEN, were also evaluated in antibacterial potentiation assays. While EDTA (MIC 500 μΜ) showed changes in antibacterial activities with metal(II) cations, TPEN showed only 2- to 4-fold reduction in antibacterial activities against S. aureus 29213. The dramatic metal(II) cation potentiation or suppression of antibacterial activities is unique, complex, and in some instances follows no predictable trends (i.e., mixed copper(II) potentiation results). It is likely that the exemplified quinoline compounds bind all metal(II) cations tested in these studies, resulting in differential antibacterial activities. The observed metal(II) activation of exemplified quinoline compounds plays a primary role in their antibacterial mechanism which has excellent potential for antibacterial therapies of biofilm-associated bacteria.
Kill Kinetics for Halogenated Quinoline 1 against S. aureus 29213:
[00275] An overnight culture of Staphylococcus aureus ATCC 29213 was diluted
1: 1,000 in 10 mL of LB media in test tubes containing test compounds to make final concentrations of 2x, 4x, 8x and 16x MIC for quinoline compound 1 (Figure 5)(MIC for quinoline compound 1 was 0.39 μΜ for this experiment) or vancomycin at 8x MIC (Figure 6)(3.13 μΜ; bactericidal control). These test tubes were incubated at 37 °C with shaking at 250 rpm. At time points 0, 1, 3, 6, 9 and 24 hours, aliquots were removed from the test tubes, diluted and 100 μΐ^ spread on LB agar. The resulting plates were incubated at 37 °C overnight to allow colonies to grow. Following incubation, bacterial colonies were counted on each agar plate to determine CFU/mL. Agar plates containing 30 to 300 colonies were used to plot kill curves. Each experiment was done in duplicate two separate bacterial colonies. Each kill curve was generated on separate days and slight deviations with starting CFU/mL were observed. Compounds are considered to be either bactericidal when there is a >3-logio CFU/mL decrease compared to the vehicle (DMSO) control (i.e., see vancomycin) or bacteriostatic when there is <3-logio CFU/mL decrease compared to the vehicle (DMSO) control after 24 hours (i.e., quinoline compound 1). Kill curves were plotted using Graphpad Prism 6.0.
LDH Release Assay for HeLa Cytotoxicity Assessment:
[00276] HeLa cytotoxicity was assessed using the LDH release assay described by
CytoTox96 (Promega G1780). HeLa cells were grown in Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% Fetal Bovine Serum (FBS) at 37°C with 5% C02. When the HeLa cultures exhibited 70-80% confluence, halogenated quinolines were then diluted by DMEM (10% FBS) at concentrations of 25, 50 and 100 μΜ and added to HeLa cells. Triton X-100 (at 2% v/v) was used as the positive control for maximum lactate dehydrogenate (LDH) activity in this assay (i.e., complete cell death) while "medium only" lanes served as negative control lanes (i.e., no cell death). DMSO was used as our vehicle control. HeLa cells were treated with compounds for 24 hours and then 50
Figure imgf000093_0001
of the supernatant was transferred into a fresh 96-well plate where 50 μΐ^ of the reaction mixture was added to the 96-well plate and incubated at room temperature for 30 minutes. Finally, 50 μL· of the Stop Solution is added to the incubating plates and the absorbance was measured at 490 nm.
[00277] All halogenated quinolines were found to demonstrate excellent toxicity profiles (i.e., IC 50 values >100 μΜ in LDH release assay) and gave selective indexes (S.I.) between >8 to >256 when comparing HeLa IC50 values to S. aureus 29213 MIC values. Nitroxoline 17, an antibacterial agent used to treat urinary tract infections (A. Sobke, M. Klinger, B. Hermann, S. Sachse, S. Nietzsche, O. Makarewicx, P. M. Keller, W. Pfister, E. Straube, Antimicrob. Agents Chemother. 2012, 56, 6021-6025), reported an IC50 -100 μΜ against HeLa cells in LDH release assays and demonstrating an S.I. of 4.
Antibacterial Activity Evaluation of Quinoline Compounds
[00278] The exemplified quinolines were evaluated for their abilities to inhibit bacterial growth in microdilution MIC experiments head-to-head against bromophenazine 1 (positive control) using a panel of four clinically relevant pathogens: S. aureus ATCC 29213, S. epidermidis ATCC 12228, A. baumannii ATCC 19606 and P. aeruginosa PAOl/BAA-47. This panel of pathogens included both gram-positive (S. aureus and S. epidermidis) and gram-negative (A. baumannii and P. aeruginosa) bacteria to determine the spectrum of activity of the exemplified quinolines. In addition to ATCC strains, these quinolines were evaluated against several S. aureus clinical isolates, including several methicillin-resistant S. aureus isolates and a S. epidermidis clinical isolate.
Table 4. Antibacterial and biofilm dispersion activities of exemplified quinolines against 5. aureus and 5. epidermidis.
Λ. aureus Λ. aureus S. epi. S. epi.
Compound antibacterial biofilm antibacterial biofilm
activity dispersion activity dispersion MIC (μΜ) ECso ^M) MIC (μΜ) ECso ^M)
Bromophenazine 1.56 3.76 0.78-1.56 11.6
4 12.5 9.49 12.5 14.0
5 12.5 14.9 12.5 >200
1 0.39 2.60 0.78-1.56 9.2
12 3.13-6.25 6.55 3.13 11.8
14 6.25 13.6 3.13 5.6*
21 0.39-0.78 2.55 0.39-0.78 12.8
Al 0.78-1.56 2.09 1.56 3.3
A2 1.56 2.06 >100 >200
A3 6.25 3.30 3.13 12.3 nitroxoline 25 10.5 12.5-25 14.2
[a] 5. aureus strain ATCC 29213 used for MIC. [b] 5. aureus strain MRSA-2 used for biofilm dispersion, [c] 5. epidermidis strain ATCC 12228 used for MIC and biofilm dispersion. *EC50 value obtained for a biofilm dispersal agent that demonstrates 51+1% biofilm dispersion at 200 μΜ compared to DMSO controls. All other biofilm dispersal agents were >80% effective in biofilm dispersion assays against 5. epidermidis ATCC 12228. Table 5. Biofilm inhibition assay results for exemplified quinolines and
antibiotic controls against S. aureus (ATCC 29213).
5. aureus [ ] 5. aureus
Compound antibacterial [a] MIC:IC50 Phenotype
activity biofilm Ratio
MIC (μΜ) inhibition
ICso
(μΜ)
1 6.25-12.5 1.22 7.7 Antibacterial
2 12.5 2.55 4.9 Antibacterial
3 >100 3.49 >28.7 Biofilm Inhibition
4 6.25 1.14 5.5 Antibacterial
5 6.25 0.89 7.0 Antibacterial
6 >100 4.45 >22.5 Biofilm Inhibition
7 6.25 0.76 8.2 Antibacterial
8 6.25-12.5 2.66 3.5 Antibacterial
9 >100 >100 Inactive
10 3.13 1.03 3.0 Antibacterial
11 6.25 1.06 5.9 Antibacterial
nitroxoline 25 6.50 3.8 Antibacterial
TPEN 62.5 34.8 1.8 Antibacterial
erythromycin 1.56-3.13 0.30 7.8 Antibacterial
vancomycin 1.56 0.51 3.1 Antibacterial
[a] 5. aureus strain ATCC 29213 was used to obtain MIC and IC50 values from same biofilm inhibition experiment (assay optimized for biofilm formation).
EQUIVALENTS AND SCOPE
[00279] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[00280] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[00281] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[00282] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is:
1. A pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient, wherein the potentiating agent comprises a catechol moiety.
2. The pharmaceutical composition of claim 1, wherein the quinoline is a halogenated quinoline.
3. The pharmaceutical composition of claim 1 or 2, wherein the quinoline comprises at least one N02 substituent.
4. The pharmaceutical composition of any one of claims 1-3, wherein the potentiating agent is gallic acid, caffeic acid, or tiron.
5. The pharmaceutical composition of any one of claims 1-3, wherein the potentiating agent is gallic acid.
6. The pharmaceutical composition of any one of claims 1-3, wherein the potentiating agent is caffeic acid.
7. The pharmaceutical composition of any one of claims 1-6 further comprising a second antimicrobial agent.
8. The pharmaceutical composition of claim 7, wherein the second antimicrobial agent is a beta-lactam, sulfonamide, aminoglycoside, tetracycline, chloramphenicol, macrolide, glycopeptide, oxazolidinone, ansamycin, quinolone, streptogramin, or lipopeptide.
9. The pharmaceutical composition of claim 7, wherein the second antimicrobial agent is methicillin, tigecycline, amikacin, ampicillin, or sulbactam.
10. The pharmaceutical composition of any one of claims 1-9, wherein the quinoline is of Formula (I):
Figure imgf000099_0001
or a pharmaceutically acceptable salt thereof,
wherein
each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently hydrogen, halogen, -CN, -N02, -N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORA, -N(RB)2, -SRA, -C(=0)Rc, -C(=0)ORA, -OC(=0)Rc, -C(=0)N(RB)2, -NRBC(=0)Rc, -OC(=0)N(RB)2, -NRBC(=0)ORA, - NRBC(=0)N(RB)2, S(=0)Rc, -S02Rc, -NRBS02Rc, or -S02N(RB)2;
each instance of RA is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur;
each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; each instance of R is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
11. The pharmaceutical composition of claim 10, wherein at least one of R and RJ is halogen.
12. The pharmaceutical composition of any one of claims 10-11, wherein at least one of R1, R2, and R3 is not hydrogen.
13. The pharmaceutical composition of any one of claims 10-11, wherein one of R , R , and R is not hydrogen.
14. The pharmaceutical composition of any one of claims 10-11, wherein two of R , R , and R are not hydrogen.
15. The pharmaceutical composition of any one of claims 10-11, wherein R , R", and R are not hydrogen.
16. The pharmaceutical composition of any one of claims 10-15, wherein the quinoline is of Formula (II):
Figure imgf000100_0001
or a pharmaceutically acceptable salt thereof.
17. The pharmaceutical composition of any one of claims 10-15, wherein the quinoline is of Formula (III):
Figure imgf000100_0002
or a pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition of any one of claims 10-15, wherein the quinoline is of Formula (IV):
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition of any one of claims 10-15, wherein the quinoline is of Formula (V):
Figure imgf000101_0002
or a pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition of any one of claims 10- 19, wherein R1 is optionally substituted alkyl.
21. The pharmaceutical composition of any one of claims 10-19, wherein R1 is optionally substituted C1-6 alkyl.
22. The pharmaceutical composition of any one of claims 10- 19, wherein R1 is unsubstituted C1-6 alkyl.
23. The pharmaceutical composition of any one of claims 10-19, wherein R1 is methyl.
24. The pharmaceutical composition of any one of claims 10-23, wherein R is optionally substituted alkyl.
25. The pharmaceutical composition of any one of claims 10-23, wherein R is optionally substituted C1-6 alkyl. 2
26. The pharmaceutical composition of any one of claims 10-23, wherein R is unsubstituted Ci_6 alkyl.
2
27. The pharmaceutical composition of any one of claims 10-23, wherein R is methyl.
2
28. The pharmaceutical composition of any one of claims 10-23, wherein R is optionally substituted acyl.
29. The pharmaceutical composition of any one of claims 10-23, wherein R is of the Formula (i):
Figure imgf000102_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORA, or -N(RB)2;
RA is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and
each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
30. The pharmaceutical composition of claim 29, wherein R is optionally substituted C1-6 alkyl.
31. The pharmaceutical composition of claim 29, wherein R is unsubstituted C1-6 alkyl.
32. The pharmaceutical composition of claim 29, wherein R is methyl or ethyl.
33. The pharmaceutical composition of claim 29, wherein R is optionally substituted phenyl.
34. The pharmaceutical composition of claim 29, wherein R is unsubstituted phenyl.
The pharmaceutical composition of any one of claims 10-34, wherein R4 is N02.
The pharmaceutical composition of any one of claims 10-34, wherein R4 is halog
37. The pharmaceutical composition of any one of claims 10-34, wherein R4 is CI.
38. The pharmaceutical composition of any one of claims 10-34, wherein R4 is Br.
39. The pharmaceutical composition of any one of claims 10-34, wherein R4 is I.
40. The pharmaceutical composition of any one of claims 10-39, wherein R5 is hydrogen.
The pharmaceutical composition of any one of claims 10-39, wherein R5 is halog
42. The pharmaceutical composition of any one of claims 10-39, wherein R5 is CI.
43. The pharmaceutical composition of any one of claims 10-39, wherein R5 is Br.
44. The pharmaceutical composition of any one of claims 10-39, wherein R5 is I.
45. The pharmaceutical composition of any one of claims 10-44, wherein R6 is hydrogen.
46. The pharmaceutical composition of any one of claims 10-44, wherein R6 is of the
Formula (ii):
Figure imgf000103_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
47. The pharmaceutical composition of claim 46, wherein R is optionally substituted alkyl.
48. The pharmaceutical composition of claim 47, wherein R is optionally substituted Ci_6 alkyl.
49. The pharmaceutical composition of claim 48, wherein R is unsubstituted Ci_6 alkyl.
50. The pharmaceutical composition of claim 49, wherein R is methyl or ethyl.
51. The pharmaceutical composition of claim 49, wherein R is n-propyl or isopropyl.
52. The pharmaceutical composition of claim 46, wherein R is optionally substituted heteroaryl.
53. The pharmaceutical composition of claim 52, wherein R is optionally substituted monocyclic heteroaryl.
54. The pharmaceutical composition of claim 53, wherein R is optionally substituted 5- membered heteroaryl.
55. The pharmaceutical composition of claim54, wherein R is optionally substituted furanyl.
56. The pharmaceutical composition of claim 55, wherein R is optionally substituted 2- furanyl.
57. The pharmaceutical composition of claim 55, wherein R is optionally substituted 3- furanyl.
58. The pharmaceutical composition of any one of claims 1-10, wherein the quinoline compound is of the formula:
Figure imgf000105_0001
or a pharmaceutically acceptable salt thereof.
59. The pharmaceutical composition of any one of claims 1-10, wherein the quinoline compound is of the formula:
Figure imgf000106_0001
or a pharmaceutically acceptable salt thereof.
60. A method of preventing or treating an infectious disease comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 1-59.
61. The method of claim 60, wherein the infectious disease is a bacterial infection.
62. The method of claim 61, wherein the bacterial infection is a Gram- negative bacterial infection.
63. The method of claim 62, wherein the Gram-negative bacterium is A. baumannii or K. pneumonia.
64. The method of claim 61, wherein the bacterial infection is a Gram-positive bacterial infection.
65. The method of claim 64, wherein the Gram-positive bacterium is S. aureus or S. epidermidis.
66. The method of claim 61, wherein the bacterium is an antibiotic-resistant strain.
67. The method of claim 66, wherein the bacterium is methicillin-resistant
Staphylococcus aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE).
68. The method of claim 61, wherein the bacterium is an antibiotic-susceptible strain.
69. The method of claim 68, wherein the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, sulfonamides,
aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides,
oxazolidinones, ansamycins, quinolones, streptogramins, and lipopeptides.
70. The method of claim 68, wherein the bacterium is susceptible to one or more antibiotics selected from the group consisting of methicillin, tigecycline, amikacin, ampicillin, and sulbactam.
The method of claim 60, wherein the infectious disease is a fungal infection.
72. The method of claim 60, wherein the infectious disease is a parasital infection.
73. The method of claim 60, wherein the infectious disease is a protozoan infection.
74. The method of claim 60, wherein the infectious disease is associated with the formation of a biofilm.
75. The method of any one of claims 60-74, wherein the subject is a human.
76. The method of any one of claims 60-74, wherein the subject is a patient diagnosed with cystic fibrosis.
77. A method for killing a bacterium comprising contacting the bacterium with the pharmaceutical composition of any one of claims 1-59.
78. A method for inhibiting bacterial cell growth comprising contacting the bacterium with the pharmaceutical composition of any one of claims 1-59.
79. A method for inducing bacterial hypersusceptibility comprising contacting a bacterium with the pharmaceutical composition of any one of claims 1-59.
80. The method of any one of claims 77-79, wherein the bacterium is contacted with the pharmaceutical composition in vitro.
81. The method of any one of claims 77-79, wherein the bacterium is contacted with the pharmaceutical composition in vivo.
82. A method of preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-59.
83. A method of eradicating a biofilm comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-59.
84. A kit for treating or preventing an infectious disease in a subject, wherein the kit comprising: a container comprising the pharmaceutical composition of any one of claims 1- 59; and instructions for administering the pharmaceutical composition to the subject.
85. A kit for preventing biofilm formation in a subject, wherein the kit comprising a container comprising the pharmaceutical composition of any one of claims 1-59; and instructions for administering the pharmaceutical composition to the subject.
86. A kit for treating biofilm formation on an object, wherein the kit comprising a container comprising the pharmaceutical composition of any one of claims 1-59; and instructions for applying the pharmaceutical composition to the object.
87. A kit for eradicating a biofilm, wherein the kit comprising a container comprising the pharmaceutical composition of any one of claims 1-59; and instructions for applying the pharmaceutical composition to the object.
88. A compound of Formula (C-I):
Figure imgf000109_0001
or a pharmaceutically acceptable salt thereof,
wherein
each of R IE , R 2E , and R 3E is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, or optionally substituted acyl;
4E
R is hydrogen, halogen, or -N02;
R 5E is hydrogen, halogen, or -N02;
R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group; and
provided that R 4E is halogen or N02.
89. The compound of claim 88, wherein each of R , R , and R is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted acyl.
The compound of claim 88 or 89, wherein the compound is of Formula (C-II):
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof.
91. The compound of claim 88 or 89, wherein the compound is of Formula (C-III):
Figure imgf000110_0002
or a pharmaceutically acceptable salt thereof.
92. The compound of claim 88 or 89 wherein the compound is of Formula (C-IV):
Figure imgf000110_0003
or a pharmaceutically acceptable salt thereof.
93. The compound of claim 88 or 89, wherein the compound is of Formula (C-V):
Figure imgf000110_0004
or a pharmaceutically acceptable salt thereof.
The compound of any one of claims 88-93, wherein R is unsubstituted Ci_6 alkyl.
95. The compound of any one of claims 88-93, wherein R1E is methyl.
The compound of any one of claims 88-95, wherein R is unsubstituted C1-6 alkyl.
The compound of any one of claims 88-95, wherein R is methyl.
The compound of any one of claims 88-95, wherein R is optionally substituted
99. The compound of any one of claims 88-95, wherein R is of the Formula (iii)
0
K (in)
wherein
8E
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORA, or -N(RB)2;
RA is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and
each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
100. The compound of any one of claims 88-99, wherein 4E
R is N02.
101. The compound of any one of claims 88-99, wherein 4E
R is halogen.
102. The compound n of any one of claims 88-101, wherein 5E
R is hydrogen.
103. The compound of any one of claims 88-101, wherein 5E
R is halogen.
104. The compound of any one of claims 88-103, wherein 6E
R is hydrogen.
105. The compound of any one of claims 88-103, wherein R is of the Formula (iv):
Figure imgf000112_0001
wherein
R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
106. The compound of claim 105, wherein R 7E is optionally substituted alkyl.
107. The compound of claim 106, wherein R 7E is unsubstituted alkyl.
108. The compound of claim 106, wherein R 7E is methyl, ethyl, n-propyl, or isopropyl.
109. The compound of claim 105, wherein R is optionally substituted heteroaryl.
110. The compound of claim 105, wherein R 7E is optionally substituted 5-membered heteroaryl.
111. The compound of claim 110, wherein R 7E is optionally substituted furanyl.
112. The compound of claim 111, wherein R 7E is optionally substituted 2-furanyl.
113. A pharmaceutical composition comprising a compound of any one of claims 88-112, and a pharmaceutically acceptable carrier or excipient.
114. A method of preventing or treating an infectious disease comprising administering to a subject in need thereof a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
115. A method for killing a bacterium comprising contacting the bacterium with a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
116. A method for inhibiting bacterial cell growth comprising contacting the bacterium with a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
117. method for inducing bacterial hypersusceptibility comprising contacting a bacterium with a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
118. A method of preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
119. A method of eradicating a biofilm comprising administering to a subject in need thereof a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113.
120. A kit comprising: a container comprising a compound of any one of claims 88-112 or a pharmaceutical composition of claim 113; and instructions for using the compound or pharmaceutical composition.
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CN112891334A (en) * 2021-01-19 2021-06-04 浙江大学 Application of caffeic acid derivatives in preparation of medicine for treating gonorrhea
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WO2023023647A3 (en) * 2021-08-19 2023-03-30 Haus Bioceuticals, Inc. Compositions and methods for bimodal anti-viral combination therapy
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