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WO2011034971A1 - Composés fluoroquinolone modifiés et leurs procédés d'utilisation - Google Patents

Composés fluoroquinolone modifiés et leurs procédés d'utilisation Download PDF

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Publication number
WO2011034971A1
WO2011034971A1 PCT/US2010/048996 US2010048996W WO2011034971A1 WO 2011034971 A1 WO2011034971 A1 WO 2011034971A1 US 2010048996 W US2010048996 W US 2010048996W WO 2011034971 A1 WO2011034971 A1 WO 2011034971A1
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Prior art keywords
oxo
compound
fluoro
cyclopropyl
piperazin
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PCT/US2010/048996
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English (en)
Inventor
David H. Peyton
Steven J. Burgess
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Portland State University
Designmedix Inc
Oregon State
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Portland State University
Designmedix Inc
Oregon State
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Publication of WO2011034971A1 publication Critical patent/WO2011034971A1/fr
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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

Definitions

  • the invention disclosed herein generally relates to compositions comprising modified fluoroquinolone compounds and methods of using the same for treatment of bacterial infections.
  • Embodiments of the invention relate to modified fluoroquinolone (MFQ) compounds and methods of using the same.
  • the MFQ compound includes a fluoroquinolone base structure of the formula (I):
  • X 1 is nitrogen or carbon
  • X 2 is hydrogen, a halogen, or an alkoxy group having 1-6 carbons in the alkyl part;
  • X 3 is a straight-chain or branched alkyl group with 1 to 6 carbons optionally having a substituted halogen on the terminal carbon, a phenyl, a substituted phenyl, or a cycloalkane having 1 to 6 carbons; or
  • X 2 and X 3 together form a 6-membered ring that can include one or more heteroatoms (such as N, O or S) at any position that valence requirements permit;
  • Ring 1 is a three-, four-, five-, six-, or seven-membered aliphatic ring, heterocyclic ring with one or more heteroatoms, aryl ring or heteroaryl ring, or a polycyclic ring comprising the same;
  • n is a hydrogen, an alkyl group having 1-6 carbon atoms, a halo, a haloalkyl, an amino, a hydroxyl, an alkoxy, an alkylamino, or an arylamino; n is 0 to 4 (such as 0 to 2, 1 or 2, or 1); n is 0 to 2 (all ring valences are filled by H where m and/or n is 0); and
  • X 5 is carbon or nitrogen
  • Ring 1 has the formula of (II):
  • X 6 is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms
  • R 1 and R 2 are independently selected from a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and comprising at least one heteroatom, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, or
  • R 1 and R2 together with N form a monocyclic ring or a polycyclic ring system.
  • 3 ⁇ 4 is selected from the group of: an alkyl, an alkoxy, an alkylamino, -N-, or— O-.
  • R 1 and R 2 independently have the structural formula of (IV):
  • X 7 is selected from halo, haloalkyl, amino, hydroxyl, hydroxyalkyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, keto, and carboxyl;
  • s is an integer from zero to 5;
  • Y 2 is selected from C, S, or N.
  • (X 7 ) s is selected from fluoro, chloro, trifluoromethyl, methoxy, amine, carboxyl, sulfonamide, and hydroxylalkyl.
  • Y 2 is nitrogen.
  • R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are different.
  • R 1 and R 2 together with N form a monocyclic ring.
  • R 1 and R 2 together with N form the central ring of a polycyclic ring system.
  • R 1 and R2 together with N form a ring structure
  • the central ring formed by R 1 , R 2 , and N is a 5-, 6-, or 7-membered ring.
  • the polycyclic ring system comprised of R 1 , R 2 and N has the structure (V):
  • (X 9 ) q and (Xg) t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;
  • q is an integer from zero to 4.
  • t is an integer from zero to 4.
  • each of the peripheral rings can independently include at least one heteroatom at any position that valence requirements permit.
  • the polycyclic ring system comprised of R 1 , R 2 and N has the structure (VI):
  • Y 2 is selected from NR 4 , O, and S, and wherein R4 is selected from H, lower alkyl and acyl;
  • (X9>q and (Xe)t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;
  • q is an integer from zero to 4.
  • t is an integer from zero to 4.
  • each of the peripheral rings can independently include at least one heteroatom at any position that valence requirements permit.
  • the polycyclic ring system comprised of R 1 , R 2 and N has the structure (VII):
  • Y2 is selected from NR4, O, and S, and wherein R4 is selected from H, lower alkyl and acyl;
  • (Xs))q and (Xa)t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;
  • q is an integer from zero to 4.
  • t is an integer from zero to 4.
  • each of the peripheral rings can independently include at least one heteroatom at any position that valence requirements permit.
  • the piperazine group of the fluoroquinolone base structure of the formula (I) can be modified as represented by the formula (VI):
  • X 6 is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms
  • R 1 and R 2 independently are a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and containing one or more heteroatoms such as oxygen, nitrogen or sulfur, a cycloalkyl, a heterocyclyl, an aryl (such as a substituted or unsubstituted phenyl or benzyl), and a heteroaryl (such as a pyridyl, a pyridylalkyl, a pyrazinyl, a furyl, or an indolyl), or
  • R 1 and R 2 together with N form a monocyclic ring or a poly cyclic ring system, such as a bicyclic or tricyclic ring system;
  • u is from 0 to 2.
  • the compound is one selected from the group of: 1- cyclopropy l-7-(4-(2-(diethy lamino)-2-oxoethy l)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-7-(4-(2-(cyclopropylamino)-2- oxoemyl)piperazm-1-yl)-6-fluoro-4-oxo-1,4-dmydroquinoline-3-carbox lic acid; 1-cyclopropyl- 6-fluoro-4-oxo-7-(4-(2-oxo-2-(4-(trifluoromethy l)phenyIamino)ethyl)piperazin- 1 -yl)- 1 ,4- dihydroquinoline-3-carboxylic acid; 9-fluoro-3-methyl-7-
  • the salt of the compound is a pharmaceutically acceptable salt.
  • Embodiments of the invention also relate to a pharmaceutical composition containing a therapeutically effective emount of an MFQ compound as disclosed herein, or a prodrug or salt thereof.
  • the pharmaceutical composition includes an inert pharmaceutical carrier in admixture with the compound.
  • the pharmaceutical composition includes a sterile or physiologically isotonic aqueous solution.
  • the MFQ compound, or prodrug or salt thereof is present in the pharmaceutical composition in an amount of from about 0.5% to about 90% (w/w).
  • kits comprising an MFQ compound as disclosed herein, or a prodrug or salt thereof, is provided.
  • a medicament in dosage unit form wherein the medicament contains a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof.
  • the dosage unit form is one selected from the group of: a tablet, a pill, a capsule, an ampule and a suppository.
  • Embodiments of the invention can relate to a method of treating an infection in a subject, wherein the method includes: administering a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, to said subject, wherein the administration of a therapeutically effective amount of compound results in a diminishment of infection.
  • Embodiments of the invention are also directed to the use of a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, in the manufacture of a medicament for treatment of a bacterial infection.
  • embodiments of the invention are directed to a method of preventing or reducing the likelihood of developing an infection in a subject, wherein the method includes: administration of a therapeutically-effective amount of an MFQ compound, or a prodrug or salt thereof, to said subject, wherein the administration of a therapeutically effective amount of compound results in a reduced likelihood of infection relative to that of a subject who has not received an administration of compound.
  • Embodiments of the invention are also directed to the use of a therapeutically effective emount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, in the manufacture of a medicament for treatment of an infection.
  • the infection is caused by Acinetobacter spp.
  • the infection is caused by Actinomycetes spp.
  • the infection is caused by Arthrobacter spp.
  • the infection is caused by Bacillus spp.
  • the infection is caused by Bacteroides spp.
  • the infection is caused by Bordetella spp.
  • the infection is caused by Borrelia spp.
  • the infection is caused by Branhamella spp.
  • the infection is caused by Brucella spp.
  • the infection is caused by Burkholderia spp.
  • the infection is caused by Buttlauxella spp.
  • the infection is caused by Cedecea spp.
  • the infection is caused by Cepacia spp.
  • the infection is caused by Chlamydia spp.
  • the infection is caused by Citrobacter spp. [00 1] In some embodiments, the infection is caused by Clostridium spp.
  • the infection is caused by Coxiella spp.
  • the infection is caused by Edwardsiell spp.
  • the infection is caused by Enterobacter spp.
  • the infection is caused by Enterobacteriaceae spp.
  • the infection is caused by Enterococcus spp.
  • the infection is caused by Erwinia spp.
  • the infection is caused by Escherichia spp.
  • the infection is caused by Erysipelothrix spp.
  • the infection is caused by Ewingella spp.
  • the infection is caused by Francisella spp.
  • the infection is caused by Fusospiro carte spp.
  • the infection is caused by Gardenerella spp.
  • the infection is caused by Haemophilus spp.
  • the infection is caused by Hafnia spp.
  • the infection is caused by Klebsiella spp.
  • the infection is caused by Kluyvera spp.
  • the infection is caused by Legionella spp.
  • the infection is caused by Listeria spp.
  • the infection is caused by Micrococcus spp.
  • the infection is caused by Morganella spp.
  • the infection is caused by Mycobacteria spp.
  • the infection is caused by Mycoplasma spp.
  • the infection is caused by Neisseria spp.
  • the infection is caused by Pasteurella spp.
  • the infection is caused by Peptostreptococcus spp .
  • the infection is caused by Proteus spp.
  • the infection is caused by Providencia spp.
  • the infection is caused by Pseudomonas spp.
  • the infection is caused by Rahnella spp.
  • the infection is caused by Rickettsia spp.
  • the infection is caused by Salmonella spp.
  • the infection is caused by Serratia spp.
  • the infection is caused by Shigella spp.
  • the infection is caused by Spirillum spp.
  • the infection is caused by Spirochaeta spp.
  • the infection is caused by Staphylococcus spp.
  • the infection is caused by Streptobacillus spp.
  • the infection is caused by Streptococcus spp.
  • the infection is caused by Streptomyces spp.
  • the infection is caused by Tatumella spp.
  • the infection is caused by Treponema spp.
  • the infection is caused by Trichomonas spp.
  • the infection is caused by Ureaplasma spp.
  • the infection is caused by Vaginalis spp.
  • the infection is caused by Vibrio spp.
  • the infection is caused by Xanthomonas spp.
  • the infection is caused by Yersinia spp.
  • the infection is caused by Acinetobacter baumannii
  • the infection is caused by Bacillus anthracis.
  • the infection is caused by Bacillus cereus.
  • the infection is caused by Bacillus subtilis.
  • the infection is caused by Bacteroides fragilis.
  • the infection is caused by Branhamella catarrhalis.
  • the infection is caused by Brucella melitensis.
  • the infection is caused by B rkholderia mallei.
  • the infection is caused by Burkholderia pseudomallei.
  • the infection is caused by Chlamydia psittaci.
  • the infection is caused by Citrobacter diversu .
  • the infection is caused by Citrobacter freundii.
  • the infection is caused by Clostridium Botulinum.
  • the infection is caused by Clostridium difficile.
  • the infection is caused by Clostridium perfringens.
  • the infection is caused by Clostridium tetani.
  • the infection is caused by Coxiella burnetii.
  • the infection is caused by Enterobacter aerogenes.
  • the infection is caused by Enterobacter cloacae.
  • the infection is caused by Enterococcus faecalis.
  • the infection is caused by Enterococcus faecium.
  • the infection is caused by Escherichia coli.
  • the infection is caused by Francisella tularensis.
  • the infection is caused by Haemophilus influenzae.
  • the infection is caused by Klebsiella oxytoca.
  • the infection is caused by Klebsiella pneumoniae.
  • the infection is caused by Listeria monocytogenes.
  • the infection is caused by Morganella morganii.
  • the infection is caused by Mycobacterium tuberculosis.
  • the infection s caused by Neisseria gonorrhea.
  • the infection s caused by Neisseria meningitidis.
  • the infection s caused by Proteus mirabilis.
  • the infection s caused by Proteus vulgaris.
  • the infection s caused by Providencia rettgeri is caused by Providencia rettgeri.
  • the infection s caused by Providencia stuartii is caused by Providencia stuartii.
  • the infection s caused by Pseudomonas aeruginosa.
  • the infection s caused by Rickettsia prowazekii is caused by Rickettsia prowazekii.
  • the infection s caused by Salmonella bongori.
  • the infection s caused by Salmonella choleraesuis.
  • the infection s caused by Salmonella enterica.
  • the infection s caused by Serratia marcescens is caused by Serratia marcescens.
  • the infection s caused by Shigella boydii is caused by Shigella boydii.
  • the infection s caused by Shigella dysenteriae.
  • the infection s caused by Shigella flexneri.
  • the infection s caused by Shigella sonnet.
  • the infection s caused by Staphylococcus aureus.
  • the infection s caused by Staphylococcus epidermis.
  • the infection is caused by Staphylococcus haemolyticus.
  • the infection is caused by Staphylococcus hominis.
  • the infection is caused by Staphylococcus saprophyticus.
  • the infection is caused by coagulese-negative staphylococci.
  • the infection is caused by Stenotrophomonas maltophilia. [01 1] In some embodiments, the infection is caused by Streptococcus agalactia .
  • the infection is caused by Streptococcus mutans.
  • the infection is caused by Streptococcus pneumoniae.
  • the infection is caused by Streptococcus pyogenes.
  • the infection is caused by Vibrio cholerae.
  • the infection is caused by V. vulnificus.
  • the infection is caused by Xanthomonas maltophilia.
  • the infection is caused by Yersinia pestis.
  • Figure 1 includes chemical structures that illustrate embodiments of the modified fluoroquinone compounds (MFQs) as disclosed herein.
  • Figures 2-11 include chemical structures that illustrate embodiments of modifications to the fluoroquinolone base structure as disclosed herein.
  • Figure 12 is a bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC 5 0) for various MFQ compounds on Gram-positive bacteria.
  • Figure 13 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (ICso) for various MFQ compounds on several different strains of methicillin-resistant Staphylococcus aureus (MRSA).
  • Figure 14 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC50) for various MFQ compounds on several different strains of Escherichia coli.
  • Figure 15 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC50) for various MFQ compounds on Gram-negative bacteria.
  • Figure 16 is a bar graph illustrating the measured cytotoxicity for various MFQ compounds on HepG2 cells.
  • Embodiments of the invention are directed to modified fluoroquinolone (MFQ) compounds that are effective at inhibiting bacterial growth and are useful in the treatment and prevention of bacterial infections. Also disclosed herein are methods of preparing the MFQ compounds in a pharmaceutical composition and methods of using the same to treat an infection caused by one or more bacteria species.
  • MFQ modified fluoroquinolone
  • treating encompasses relieving the disease, e.g., causing regression of the disease or its clinical symptoms.
  • the term "preventing” or “prevention,” with respect to a disease or particular condition encompasses reducing the likelihood of acquiring or developing the disease or particular condition, including in cases where prevention is sought but is ultimately unsuccessful.
  • the term “subject” includes all animals, including humans and other animals, including, but not limited to, companion animals, farm animals and zoo animals.
  • the term “animal” can include any living multi-cellular vertebrate organisms, a category that includes, for example, a mammal, a bird, a simian, a dog, a cat, a horse, a cow, a rodent, and the like.
  • the term “mammal” includes both human and non-human mammals.
  • the term "optional" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • '3 ⁇ 4eterocyclo group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
  • Fluoroquinolones were first developed in the early 1960s. The first fluoroquinolone, nalidixic acid, was approved by the FDA in 1963 for the treatment of urinary tract infections and is considered the parent of the fluoroquinolone class of compounds. The development of other fluoroquinolones by chemically altering the base structure of nalidixic acid has led to the synthesis of a wide variety of fluoroquinolones that populate this class of structures.
  • the fluoroquinolone base structure that is modified as herein disclosed can be any fluoroquinolone known to those skilled in the art.
  • Exemplary fluoroquinolones useful in the compositions and methods of embodiments of the invention include, but are not limited to, those described in BE 870,576, U.S. Patent No. 4,448,962, DE 3,142,854, EP 047,005, EP 206,283, BE 887,574, EP 221,463, EP 140,116, EP 131,839, EP 154,780, EP 078,362, EP 310,849, EP 520,240, U.S. Patent No. 4,499,091, U.S. Patent No. 4,704,459, U.S. Patent No. 4,795,751, U.S. Patent No. 4,668,784, and U.S. Patent No. 5,532,239, each of the foregoing which is incorporated herein by reference in its entirety.
  • Exemplary fluoroquinolone compounds that can be modified include, but are not limited to, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfioxacin, trovafloxacin, tosufloxacin, temafloxacin, and sarafloxacin.
  • a fluoroquinolone compound having the structure (I) can be modified as disclosed herein:
  • X2 is hydrogen, a halogen, or an alkoxy group having 1-6 carbons in the alkyl part;
  • X3 is a straight-chain or branched alkyl group with 1 to 6 carbons optionally having a substituted halogen on the tenninal carbon, a phenyl, a substituted phenyl, or a cycloalkane having 1 to 6 carbons; or
  • X 2 and X3 together form a 6-membered ring that can include one or more heteroatoms (such as N, O or S) at any position that valence requirements permit;
  • Ring 1 is a three-, four-, five-, six-, or seven-membered aliphatic ring, heterocyclic ring with one or more heteroatoms, aryl ring or heteroaryl ring, or a polycyclic ring comprising the same;
  • X n is a hydrogen, an alkyl group having 1-6 carbon atoms, a halo, a haloalkyl, an amino, a hydroxyl, an alkoxy, an alkylamino, or an arylamino; n is 0 to 4 (such as 0 to 2, 1 or 2, or 1); n is 0 to 2 (all ring valences are filled by H where m and/or n is 0); and
  • X5 is carbon or nitrogen.
  • the fluoroquinolone base structure can be modified at any position in Ring 1 of structure ( ⁇ ).
  • a modified fluoroquinolone (MFQ) compound can have a chemical structure in which the nitrogen at position 4 of the piperazine group is modified as follows:
  • G represents a fluoroquinolone-resistance reversal agent moiety.
  • Suitable G groups include derivatives of reversal agents having one or more cyclic groups.
  • G has the structure as follows:
  • ⁇ is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms
  • R 1 and R 2 independently are a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and containing one or more heteroatoms such as oxygen, nitrogen or sulfur, a cycloalkyl, a heterocyclyl, an aryl (such as a substituted or unsubstituted phenyl or benzyl), and a heteroaryl (such as a pyridyl, a pyridylalkyl, a pyrazinyl, a furyl, or an indolyl), or
  • R 1 and R 2 together with N form a monocyclic ring or a polycyclic ring system, such as a bicyclic or tricyclic ring system.
  • 3 ⁇ 4 is alkyl (such as methyl, ethyl, propyl, i-propyl, or butyl), alkoxy (such as methoxy or ethoxy), alkylamino (such as methylamino or ethylamino), -N-, or -0-.
  • R 1 and R 2 groups include aryl groups and substituted alkyl groups, such as cyclohexyl, methylcyclohexyl (-CFfcCeHu), adamantyl, methyl adamantyl and ethyl adamantyl.
  • at least one of R 1 and R 2 is a sterically bulky group. Suitable sterically bulky groups for incorporation as R 1 and/or R 2 will be readily apparent to those of ordinary skill in the art upon consideration of the present disclosure.
  • R 1 and R 2 independently have a chemical structure as follows:
  • X7 is independently halo, haloalkyl (such as trifluoromethyl), amino, hydroxyl, hydroxyalkyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, keto, or carboxyl; s is 0 to 5 as valence requirements permit (for example, when Y 2 is nitrogen, s is from 0 to 4); Y2 is C, S, or N.
  • (X 7 ) s is independently fluoro, chloro, trifluoromethyl, methoxy, amine (e.g., -NH2), carboxyl ⁇ e.g., -COOH), sulfonamide (e.g., -SO2NH 2 ), hydroxylalkyl (e.g., -(CH2) shadow-OH, where n is 1, 2, 3, or 4), and/or s is 0 to 3, 0 to 2, or 1.
  • X 7 can be independently fluoro, chloro, trifluoromethyl, or methoxy.
  • X 7 can be independently selected from these groups for each occurrence "s.”
  • Y2 is nitrogen
  • R 1 and R 2 are the same (referred to as, symmetric). In some embodiments, R 1 and R 2 are different, such compounds are referred to herein as being asymmetric.
  • R 1 and R 2 together with N form a monocyclic ring.
  • R 1 and R 2 together with N can form a monocyclic ring that is a 5-, 6- or 7-membered ring.
  • R 1 and R 2 together with N can form a monocyclic ring with greater than 7 members.
  • R 1 and R 2 together with N form the central ring of a polycyclic ring system, such as a bicyclic or tricyclic ring system.
  • , R 2 , and N is a 5-, 6-, or 7-membered ring.
  • Exemplary structures for a tricyclic ring system formed by R 1 , R 2 , and N include, without limitation:
  • Y 2 is C, NR , O, or S
  • (X ⁇ q and (Xg)t are independently H, alkyl, halo (such as F, CI), haloalkyl (such as trifluoromethyl), alkoxy (such methoxy), amino, hydroxyl, alkylamino, cyano, or mercapto
  • R is H, lower alkyl or acyl
  • q and t are independently 0 to 4 as valence requirements permit (such as
  • ( ⁇ >) 4 and (Xs) t are independently H, methyl, fluoro, chloro, trifluoromethyl, methoxy, or cyano.
  • Y2 is N or S.
  • the piperazine group of the fluoroquinolone base can be modified as represented by the formula:
  • Fluoroquinolone resistance reversal agents suitable for incorporation as, for example "G” in the general structures presented above can be based upon knowledge of chloroquine resistance reversal agents found in the art (for example, Bhattacharjee et al. 2002. J. Chem. Inf. Comput. Sci. 42:1212-1220; Guan et al. 2002. J. Med. Chem. 45(13):2741-2748, each of the foregoing which is incorporated herein by reference in its entirety).
  • reversal agents are believed to exert their biological effect, at least in part, by decreasing the efflux of fluoroquinolone (or fluoroquinolone-like drugs) from the pathogen, which efflux is thought to be mediated by a membrane pump.
  • exemplary reversal agents include, without limitation, amitriptyline, amlodipine, azatadine, chlc ⁇ heniramine, citalopram, cyclosporine, cyproheptadine, cyproheptadine, desipramine, dibenzosuberanylpiperazine derivatives (Osa et al. 2003. /. Med. Chem. 46(10): 1948- 1956), diethyl-!
  • a fluoroquinolone-resistance reversal agent moiety as described herein includes any known reversal agent or derivative thereof that retains fluoroquinolone resistance reversal function, or any chemical structure that satisfies a fluoroquinolone resistance reversal agent pharmacophore (such as one based on the Bhattacharjee et al. pharmacophore described above) and confers fluoroquinolone resistance reversal function.
  • a fluoroquinolone resistance reversal function is the ability of a compound (or moiety) to sensitize at least one fluoroquinolone-resistant target species to a modified fluoroquinolone (MFQ) compound when the MFQ compound is modified with a reversal function.
  • MFQ modified fluoroquinolone
  • a fluoroquinolone-resistant target species is sensitized to an MFQ compound if a an MFQ compound inhibits target pathogen growth as compared to pathogen growth in the presence of fluoroquinolone compound alone.
  • pathogen growth in the presence of a an MFQ compound can be at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% less than pathogen growth in the presence of fluoroquinolone compound only.
  • a fluoroquinolone compound (such as, for example, ciprofloxacin) can be covalently linked to a fluoroquinolone-resistant reversal agent moiety via commonly known chemical syntheses.
  • Exemplary MFQ compounds include, but are not limited to, l-cyclopropyl-7- (4-(2-(diethylamino)-2-oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid ("DM1050 DP102"); l-cyclopropyl-7-(4-(2-(cyclopropylamino)-2- oxoethyl)piperazin- l-yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid (“DM1051/DP103"); l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(4- (trifluoromethyl)phenylamino)ethyl)piperazin- 1 -y ⁇ y 1 ,4-dihydroquinoline-3 -
  • Exemplary compounds also include, but are not limited to, those disclosed herein, including those illustrated in Figures 1-11.
  • Methods of MFQ compound synthesis are also include, but are not limited to, those disclosed herein, including those illustrated in Figures 1-11.
  • the disclosed MFQ compounds can be synthesized by any method known in the art. Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York:Longman, 1978).
  • Compounds as described herein may be purified by any of the means known in the art, including chromatographic means, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer- Verlag, New York, 1969.
  • Formulations for pharmaceutical compositions are well known in the art For example, Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 15 th Edition, 1975, describes exemplary formulations (and components thereof) suitable for pharmaceutical delivery of disclosed RCQ compounds.
  • Pharmaceutical compositions comprising at least one MFQ compound as disclosed herein can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition can depend, for example, on the mode of administration (e.g., oral or parenteral) and/or on the location of the infection to be treated (e.g., liver-stage and/or blood-stage for parasites).
  • formulations include a pharmaceutically acceptable carrier in addition to at least one active ingredient, such as a MFQ compound.
  • active ingredient such as a MFQ compound.
  • other medicinal or pharmaceutical agents for example, with similar, related or complementary effects on the affliction being treated can also be included as active ingredients in a pharmaceutical composition.
  • compositions typically comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • parenteral formulations typically comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can optionally contain minor amounts of non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like; for example, sodium acetate or sorbitan monolaurate.
  • excipients include, nonionic solubilizers, such as cremophor, or proteins, such as human serum albumin or plasma preparations.
  • the disclosed pharmaceutical compositions can be formulated as a pharmaceutically acceptable salt of a disclosed MFQ compound.
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids. Non-limiting examples of suitable inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydriodic acid, and phosphoric acid.
  • Non-limiting examples of suitable organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicylic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, and the like. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17 th Edition, Mack Publishing Company, Easton, PA, 1985. A pharmaceutically acceptable salt can also serve to adjust the
  • the disclosed pharmaceutical compositions can be formulated as a pro-drug of a disclosed MFQ compound.
  • Pro-drug forms of the MFQ compound include carboxylic acid ester forms, forms that incorporate amidic functions on a free nitrogen of the 7-piperazinyl group of the MFQ compound, and forms that incorporate sulfur moieties at the C-2 position of the fluoroquinolone base structure of an MFQ compound.
  • the dosage form of a disclosed pharmaceutical composition will be determined by the mode of administration chosen.
  • topical or oral dosage forms can be employed.
  • Topical preparations can include eye drops, ointments, sprays and the like.
  • Oral formulations can be liquid (e.g., syrups, solutions or suspensions), or solid (e.g., powders, pills, tablets, or capsules). Methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.
  • compositions comprising a disclosed MFQ compound can be formulated in unit dosage form suitable for individual administration of precise dosages.
  • amount of active ingredient (e.g., MFQ compound) administered will depend on the subject being treated, the severity of the affliction, and the manner of administration, and is known to those skilled in the art.
  • the formulation to be administered will contain a quantity of the extracts or compounds disclosed herein in an amount effective to achieve the desired effect in the subject being treated.
  • At least one modified fluoroquinolone (MFQ) compound, or prodrug or salt thereof is present in the pharmaceutical composition in an amount ranging from about 0.5 percent to about 90 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 1 percent to about 85 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 80 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 10 percent to about 75 percent by weight of the pharmaceutical composition.
  • MFQ modified fluoroquinolone
  • the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 15 percent to about 50 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 25 percent to about 35 percent by weight of the pharmaceutical composition.
  • the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 25 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 20 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 10 percent by weight of the pharmaceutical composition.
  • the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 15 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 10 percent by weight of the pharmaceutical composition.
  • the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 20 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 30 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 35 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 40 percent by weight of the pharmaceutical composition.
  • the pharmaceutical composition is a solution.
  • the pharmaceutical composition is injectable.
  • the pharmaceutical composition can be administered parenterally.
  • the pharmaceutical composition can be administered subcutaneously.
  • the pharmaceutical composition can be administered intravenously.
  • the pharmaceutical composition can be administered orally.
  • the pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, sweeteners, flavoring agents, preservatives, and coloring agents. Such excipients are known in the art. Examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences at pages 1447-1676 (Alfonso R. Gennaro ed., 19* ed. 1995), which is incorporated herein by reference in its entirety.
  • preservatives include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, and quaternary ammonium compounds such as benzalkonium chloride.
  • Embodiments of the invention relate to methods of treating or preventing a condition in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition as disclosed herein.
  • the method comprises administering a pharmaceutical composition comprising a disclosed MFQ compound, or prodrug or salt thereof (and, optionally, one or more other pharmaceutical agents) to a subject in a pharmaceutically acceptable carrier and in an amount effective to treat the condition.
  • the treatment can also be used prophylactically in any subject
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the subject is one selected from the group of: a companion animal, a farm animal and a zoo animal.
  • the animal is one selected from the group of: a bird, a simian, a dog, a cat, a horse, a cow, and a rodent.
  • the condition to be treated or prevented is an infection.
  • the condition to be treated or prevented is a bacterial infection.
  • the condition is an infection caused by bacteria from a variety of genera, including, but not limited to, Acinetobacter spp., Actinomycetes spp., Arthrobacter spp., Bacillus spp., Bacteroides spp., Bordetella spp., Borrelia spp., Branhamell spp., Brucella spp., Burkkolderia spp.s, Buttlauxella spp., Cedecea spp., Chlamydia spp., Citrobacter spp., Clostridium spp., Coxiella spp., Edwardsiella spp., Enterobacter spp., Enterobacteriaceae spp., Enterococcus spp., Erwinia spp
  • embodiments of the invention feature a method of treating infections by a bacteria belonging to the genera above, among others.
  • the condition can be a bacterial infection caused by bacteria including, but not limited to, Acinetobacter baumannii, Bacillus anthracis, Bacteroides fragilis, Branhamella catarrhalis, Brucella melitensis, Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Citrobacter diversus, Citrobacter freundii, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Coxiella burnetii, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Listeria monocytogenes, Morganella
  • Neisseria gonorrhea Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Rickettsia prowazekii, Salmonella bongori, Salmonella choleraesuis, Salmonella enterica, Serratia marcescens, Shigella boydii. Shigella dysenteriae. Shigella flexneri, Shigella sonnei, Staphylococcus aureus. Staphylococcus epidermis, Staphylococcus haemolyticus.
  • Staphylococcus hominis Staphylococcus saprophyticus, coagulese-negative staphylococci.
  • Streptococcus pneumoniae Streptococcus pyogenes, Vibrio cholrunge, V. vulnificus, Xanthomonas maltophilia, and Yersinia pestis.
  • Embodiments of the invention are also directed to a method of treating or preventing a condition or infection caused by a Gram-positive bacteria.
  • Gram- positive bacteria have a thick cell membrane consisting of multiple layers of peptidoglycan and an outside layer of teichoic acid.
  • Exemplary gram-positive organisms include, but are not limited to, coagulase- negative staphylococci, streptococci, enterococci, corynebacteria, and Bacillus species.
  • exemplary gram-positive bacterial infections that can be treated according to embodiments of the invention include, but are not limited to, infections by Bacillus anthracis, Bacillus cereus.
  • Bacillus subtilis Clostridium perfringens, Clostridium tetani, Clostridium botulinum, Clostridium difficile Enterococcus faecalis, Enterococcus faecium, Mycobacterium tuberculosis, Staphylococcus aureus, Staphylococcus epidermidis. Streptococcus agalactiae. Streptococcus mutans, Streptococcus pneumoniae and Streptococcus pyogenes,.
  • a method of treating or preventing a condition or infection caused by a Gram-negative bacteria is provided.
  • Exemplary gram- negative organisms include, but are not limited to, Acinetobacter spp., Burkholderia spp., Cepacia spp., Gardenerella spp., Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica, Shigella sonnei, Stenotrophomonas maltophilia, Vaginalis spp, and Vibrio cholerae.
  • multi-drug resistant strains of bacteria can be treated according to embodiments of the invention.
  • Resistant strains of bacteria include penicillin-resistant, methicillin-resistant, quinolone-resistant, macrolide-resistant, and or vancomycin-resistant bacterial strains.
  • Multi-drug resistant bacterial infections to be treated using embodiments of the invention include infections by penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Streptococcus pneumoniae', penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Staphylococcus aureus; penicillin-, methicillin-, macrolide-, vancomycin-, and or quinolone-resistant Streptococcus pyogenes; and penicillin-, methicillin-, macrolide-, vancomycin-, and or quinolone-resistant Enterococcus spp.
  • embodiments of the invention are directed to treatment or prevention of infections caused by the following bacteria: SHIGELLA SPECIES
  • Shigella species are aerobic, non-motile, glucose-fermenting, gram-negative bacterial rods that are highly contagious, causing diarrhea after ingestion of less than 100 organisms.
  • Exemplary pathogenic species include, but are not limited to, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii.
  • S. sonnei is primarily responsible for the 450,000 cases of shigellosis that occur in the U.S. each year, while S. flexneri causes the majority of the 1.8 million cases that occur globally.
  • E. coli Diarrheagenic Escherichia coli causes watery or bloody diarrhea, including traveler's diarrhea and food borne disease.
  • Exemplary Escherichia coli include many different serotypes, categorized into four major groups according to virulence mechanisms: enterotoxigenic (ETEC) (primary cause of traveler's disease); enteropathogenic (EPEC) and enteroinvasive (EIEC) (two common causes of children's disease in developing countries); and enteroaggregative (Eagg EC) (primary cause of disease in HTV patients).
  • ETEC enterotoxigenic
  • EPEC enteropathogenic
  • EIEC enteroinvasive
  • Eagg EC enteroaggregative
  • Salmonella organisms live in the intestines of most food animals. Transmission of Salmonella spp. to humans can occur by many routes, including consumption of contaminated food of animal origin (e.g. meat, poultry, eggs and milk), although many other foods, including green vegetables contaminated from manure, have been implicated. In recent years, problems related to Salmonella have increased significantly, both in terms of incidence and severity of cases of human salmonellosis. Salmonellosis is a common zoonotic disease in humans.
  • resistance to fluoroquinolones can arise from a combination of different resistance mechanisms, including, for example, mutational modifications of the target enzymes for fluoroquinolones, the DNA gyrase, and enhanced active efflux and gradually increased levels of production of the AcrAB pump, which has been found in mutants increasingly resistant to ciprofloxacin and other antibiotics (Giraud, Etienne, et al. 2000. Antimicrob Agents Chemother 44(5): 1223—1228, which is incorporated herein by reference in its entirety).
  • Routes of administration useful in the disclosed methods include but are not limited to oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, and transdermal. Formulations for these dosage forms are described above.
  • An effective amount of a MFQ compound will depend, at least, on the particular method of use, the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.
  • a "therapeutically effective amount" of a composition is a quantity of a specified compound sufficient to achieve a desired effect in a subject (host) being treated. For example, this can be the amount of a MFQ compound necessary to prevent, inhibit, reduce or relieve a condition caused by infection by a target pathogen.
  • Therapeutically effective doses (or growth inhibitory amounts) of a disclosed MFQ compound or pharmaceutical composition can be determined by one of skill in the art, with a goal of achieving local (e.g., tissue) concentrations that are at least as high as the IC 50 of the applicable compound disclosed in the examples herein.
  • the effective amount administered to the subject depends on a variety of factors including, but not limited to the age, body weight, general health, sex and diet of the subject being treated, the condition being treated, the severity of the condition, the activity of the specific MFQ compound being administered, the metabolic stability and length of action of that compound, mode and time of administration, rate of excretion and the drug combination.
  • the amount of the pharmaceutical composition that is effective in the treatment or prevention of a condition, such as a bacterial infection, can be determined by standard clinical techniques well known to those of skill in the art. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. One of ordinary skill in the art will readily be able determine the precise dose to be employed. Suitable effective dosage amounts, however, typically range from about 0.1 mg kg of body weight to about 50 mg/kg of body weight, from about 0.5 mg kg of body weight to about 25 mg kg of body weight, from about 0.75 mg/kg of body weight to about 20 mg kg of body weight, or from about 1 mg kg of body weight to about 15 mg kg of body weight.
  • the effective dosage amounts described herein refer to total amount of MFQ compound administered. For example, if more than one MFQ compound is administered, the effective dosage amounts correspond to the total amount of MFQ compound administered.
  • the pharmaceutical composition can be administered parenterally. In some embodiments, the pharmaceutical composition can be administered subcutaneously. In some embodiments, the pharmaceutical composition can be administered intravenously. In some embodiments, the pharmaceutical composition can be administered orally.
  • the pharmaceutical composition can be administered by injection, which includes, but is not limited to, the following means of delivery: intradermal; intramuscular; intraperitoneal; intravenous; and subcutaneous.
  • the effective amount of the pharmaceutical composition is administered once per day until 2-3 days after cessation of the condition.
  • the effective amount of the pharmaceutical composition is administered as two doses per day until 2-3 days after cessation of the condition.
  • the effective amount of the pharmaceutical composition is administered once per day for from about 1 to about 10 days.
  • the effective amount of the pharmaceutical composition can be administered once per day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
  • the effective amount of the pharmaceutical composition is administered as two doses per day for from about 1 to about 10 days.
  • the effective amount of the pharmaceutical composition can be administered as two doses per day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
  • the effective amount of the pharmaceutical composition is administered once per day for about 14 days.
  • the effective amount of the pharmaceutical composition is administered as two doses per day for about 14 days.
  • the effective amount of the pharmaceutical composition is administered once per day for about 21 days.
  • the effective amount of the pharmaceutical composition is administered as two doses per day for about 21 days.
  • a dosage range is from about 0.1 to about 200 mg/kg body weight orally in single or divided doses.
  • a dosage range is from about 1.0 to about 100 mg kg body weight orally in single or divided doses, including from about 1.0 to about 50 mg/kg body weight, from about 1.0 to about 25 mg kg body weight, from about 1.0 to about 10 mg/kg body weight (assuming an average body weight of approximately 70 kg; values adjusted accordingly for persons weighing more or less than average).
  • the compositions can be, for example, provided in the form of a tablet containing from about 50 to about 1000 mg of the active ingredient, particularly about 75 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, or about 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject being treated.
  • a tablet containing from about 500 mg to about 1000 mg active ingredient is administered once (e.g., a loading dose) followed by administration of 1/2 dosage tablets (e.g., from about 250 to about 500 mg) each 6 to 24 hours for at least 3 days.
  • Step 2 2-Chloro-N-(3-trifluoromethylphenyl)acetarnide (0.80 g, 0.0033 mol) was dissolved in DMF (25 mL), and ciprofloxacin (1.00 g, 0.003 mol), sodium bicarbonate carbonate (0.28 g, 0.0033 mol) and potassium iodide (0.60 g, 0.0033 mol). After stirring at 60 C for 6 days TLC (silica) indicated the reaction was complete. The reaction was cooled to room temperature and the DMF was removed under vacuum. The residue was dissolved in chloroform and washed with water. The organic layer was separated, dried over magnesium sulfate, and evaporated.
  • Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 were assayed in an initial bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the minimal inhibitory concentration that inhibits the growth of 50% of organisms (MICso). Reference antibiotics used for comparison were vancomycin hydrochloride (e.g. Sigma Cat. #V-2002) and ciprofloxacin (eg. Fluka 17850).
  • All MFQ compounds were prepared as 6.4 mg/ml stock solutions in DMSO and further diluted with sterile water or appropriate diluent. A working stock of 256pg/ml was used to perform 1:2 serial dilutions in 96-well plates. Final MIC concentrations tested in the study ranged from 64 Mg/ml to 0.12 Mg/ml.
  • Bacterial inoculums were prepared by making a direct sterile water suspension of isolated colonies from 18 to 24-hour agar plates for all organisms in Table 1 (using Mueller Hinton or Blood Agar media plates). Each bacterial suspension was adjusted for reading between 0.09 and 0.11 absorbance at 620nm (0.5 McFarland Standard). The suspensions were further diluted 1:100 in Mueller Hinton broth (MHB) for inoculating the 96- well plates. The final concentrations for Listeria monocytogenes had 3% lysed horse blood.
  • Table 2 illustrates the results of the MICso assay. The results indicate that all compounds demonstrate effective activity against the Staphylococcal species tested as well as good to moderate activity against the E. coli, Salmonella and Shigella strains included in the panel. DP- 100 (DM1021) demonstrates good to moderate activity against all organisms tested in the panel. The results indicate that MFQ compounds have effective anti-bacterial activity in vitro.
  • Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 and 7-11 were assayed in a bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the inhibitory concentration that inhibits the growth of 50% of organisms (IC50). Reference antibiotics used for comparison were vancomycin hydrochloride ⁇ e.g. Sigma Cat. #V-2002), ciprofloxacin ⁇ e.g. Fluka 17850) and rifampin.
  • Wells treated with test compounds or reference antibiotics at effective concentrations exhibited anti-bacterial activity as shown by markedly lower OD600 values.
  • Wells treated with test compounds or reference antibiotics that are not effective anti-bacterial agents illustrated little to no difference in OD600 values from the negative (untreated) control wells.
  • Table 3 provides a list of organisms used for the inhibition assay.
  • Tables 4-5 and Figures 12-16 illustrate the results of the IC 5 0 assay.
  • Figures 12-16 illustrate the dose-dependent growth inhibition curves for the test compounds listed in Tables 4-5. The results indicate that the modified compounds exhibit a reasonably broad spectrum of activity against different bacterial species and that generally, the MFQ compounds developed as disclosed herein have effective anti-bacterial activity in vitro.
  • Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 and 7-11 were assayed in a bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the rriinimal inhibitory concentration that inhibits the growth of organisms (MIC).
  • MIC rriinimal inhibitory concentration
  • Reference compounds used for comparison included linezolid (ChemPacific 35710 Lot CHPC091007-01), vancomycin (Sigma V2002 Lot 087K0694), gentamicin (Sigma 3632 Lot 047K075), cefotaxime (Sigma 7912 Lot 084K0674), ciprofloxacin (USP Rockville 1134335 Lot IOC265), imipenem (USP Rockville 1337809 Lot 3IOH217) and levofloxacin (Biochemka 446423/1).
  • the MFQ compounds were solubilized in 100% DMSO at a final concentration of 1.28 mg/ml, with the exception of DM1021 and DM1023, which fell out of solution and were applied to bacteria as a suspension. Reference compounds were solublized in sterile deionized water. Stocks were made to achieve a starting concentration in the assay of 64 g/mL. The assay was split in two parts with the Gram positive organisms tested on one day and the Gram negative organisms tested two days later. The DMSO stocks of the investigational compounds were frozen after the first assay, and then thawed at room temperature for use in the second assay. Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922 were tested on both days with all MFQ compounds in order to evaluate the effect of freeze-thaw on the potency of each compound.
  • test organisms consisted of 25 clinical isolates from the Micromyx Culture Collection (Kalamazoo, Michigan). Also included were 5 ATCC strains which provided quality control data for the assay. Table 6 lists the isolates that were tested.
  • test medium employed for the broth microdilution MIC assay was Mueller Hinton ⁇ broth (MHBII; BBL 212322, Lot 9044411).
  • the medium was supplemented with 4% laked horse blood (Cleveland Scientific Lot 27211-1) to support the growth of streptococci.
  • MIC values were determined using the CLSI- recommended broth microdilution procedure (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard— Eighth Edition. CLSI document M07-A8 [ISBN 1-56238-689-1]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009.). Automated liquid handlers (Multidrop 384, Biomek 2000 and Multimek 96; BeckmanCoulter, Brea, CA) were used to conduct serial dilutions and liquid transfers.
  • the Multidrop was used to transfer media to the daughter plates, and the Multimek 96 transferred transferred 5 ⁇ L ⁇ of drug solution from each well of a mother plate to each corresponding well of each daughter plate in a single step.
  • each well of the daughter plates contained 185 ⁇ ⁇ of MHB ⁇ 4% laked horse blood, 5 ⁇ L ⁇ of drug solution and 10 ⁇ ⁇ of bacterial inoculum.
  • each well of the daughter plates contained 85 uL of MHB II, 5 ⁇ ]_ of drug solution, and 10uL of bacterial inoculum.
  • Plates were stacked 3 high, covered with a lid on the top plate, placed in plastic bags, and incubated at 35oC for 18-20 hours. Following incubation, the microplates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth of the organism.
  • the susceptibility data obtained for Gram-positive pathogens is shown in Table 7 for each of the MFQ compounds and the seven reference compounds. Good activity was observed for most of the MFQ compounds for each of the 2 MSSA isolates tested; MIC values ranged from 0.12 ⁇ / ⁇ for compound 1066 to >64 ⁇ for compound 1101. When comparing the activity of the MFQ compounds against the 2 MSSA isolates, the MIC values were within one serial two-fold dilution of each other, and therefore a given MFQ compound had similar activity against each isolate. For S. epidermidis, each of the MFQ compounds exhibited good activity against the single MSSE isolate. In addition, Isolate 3185 (VSE. faecalis) was sensitive to the MFQ compounds.
  • Table 8 contains susceptibility data for the test agents and comparators against Gram-negative isolates.
  • MIC values 8 ⁇ g/ ⁇ ll for all such isolates.
  • compounds that produced on scale MIC values were more active against ciprofloxacin- sensitive A. baumannii, followed by E. coli, K. pneumoniae, and finally P. aeruginosa.
  • Table 9 represents susceptibility data obtained for the ATCC reference strains on each of two testing days.
  • the MFQ compounds were dissolved in DMSO on the first testing day and aliquoted for the MIC assay that day; the compounds were then frozen for future use on a second assay two days later.
  • Table 9 indicates that the majority of MFQ compounds produced similar MIC values on each of the test days, demonstrating that freeze thaw had little or no effect on compound activity.
  • a subject presents with a bacterial infection, which is identified as being caused by a methycillin-resistant strain of Stapholococcus aureus (MRSA).
  • MRSA methycillin-resistant strain of Stapholococcus aureus
  • the subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.0 mg/kg of body weight twice per day for a period of 5-7 days.
  • the bacterial infection begins to subside, and the subject presents with improved symptoms ⁇ e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.
  • a subject presents with a bacterial infection, which is identified as being caused by Shigella sonnet.
  • the subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 0.5 mg kg of body weight once daily for a period of 7-10 days.
  • the bacterial infection begins to subside, and the subject presents with improved symptoms (e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.
  • a subject presents with a bacterial infection, which is identified as being caused by Enterococcus faecium.
  • the subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.5 mg kg of body weight twice daily for a period of 7-10 days.
  • the bacterial infection begins to subside, and the subject presents with improved symptoms (e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.
  • a subject presents with a bacterial infection, which is identified as being caused by Pseudomonas aeruginosa.
  • the subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.0 mg kg of body weight twice daily for a period of 3-5 days.
  • the bacterial infection begins to subside, and the subject presents with improved symptoms ⁇ e.g. abatement of fever and fatigue, improved appetite and energy )by die end of the administration period.
  • a subject is exposed to a methycillin-resistant strain of Stapholococcus aureus (MRSA) and is presented with a risk for bacterial infection.
  • MRSA methycillin-resistant strain of Stapholococcus aureus
  • the subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.0 mg/kg of body weight twice per day for a period of 5-7 days.
  • the subject presents with milder symptoms of bacterial infection.
  • a subject is exposed to Shigella sormei and is presented with a risk for bacterial infection.
  • the subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 0.5 mg kg of body weight once daily for a period of 7-10 days.
  • the subject exhibits few to no symptoms of bacterial infection and overall presents with a healthy outlook.
  • a subject is exposed to Enterococcus faecium and is presented with a risk for bacterial infection.
  • the subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.5 mg kg of body weight twice daily for a period of 7-10 days.
  • the subject presents with full symptoms of bacterial infection.
  • the bacterial infection begins to subside, and the subject presents with improved symptoms ⁇ e.g. abatement of fever and fatigue, improved appetite and energy ) within days of regimen completion.
  • a subject is exposed to Pseudomonas aeruginosa and is presented with a risk of bacterial infection.
  • the subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein.
  • the composition is administered orally at a dose of 1.0 mg/kg of body weight twice daily for a period of 3-5 days.
  • the subject presents with bacterial infection begins to subside, and the subject exhibits no symptoms of bacterial infection and overall presents with a healthy outlook.
  • the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

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  • Medicinal Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

Des modes de réalisation de l'invention portent sur des composés fluoroquinolones modifiés (MFQ) et sur des procédés pour les utiliser dans le traitement d'une infection dans un sujet.
PCT/US2010/048996 2009-09-15 2010-09-15 Composés fluoroquinolone modifiés et leurs procédés d'utilisation Ceased WO2011034971A1 (fr)

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US8658648B2 (en) 2008-12-05 2014-02-25 Designmedix, Inc. Modified chloroquines with single ring moiety or fused ring moiety
WO2014178008A1 (fr) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Derivés de quinolone
CN108349968A (zh) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 抗菌治疗剂和预防剂
JP2020508999A (ja) * 2016-11-02 2020-03-26 アクトシオナーノエ オブシェストヴォ“タツフィムファルムプレパラティ” シプロフロキサシン誘導体系抗菌薬
RU2757741C1 (ru) * 2021-03-01 2021-10-21 Федеральное государственное бюджетное учреждение науки Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук (ИХБФМ СО РАН) Производное ципрофлоксацина, обладающее антибактериальной активностью в отношении антибиотикоустойчивых штаммов микроорганизмов
US11945800B1 (en) 2023-09-21 2024-04-02 King Faisal University 1-cyclopropyl-6-fluoro-4-oxo-7-(4-((5-oxo-2-phenyl-4-(quinolin-2-ylmethylene)-4,5-dihydro-1H-imidazol-1-yl)methyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid as an anti-inflammatory and anticancer compound

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8658648B2 (en) 2008-12-05 2014-02-25 Designmedix, Inc. Modified chloroquines with single ring moiety or fused ring moiety
WO2014178008A1 (fr) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Derivés de quinolone
US9540399B2 (en) 2013-05-02 2017-01-10 Actelion Pharmaceuticals Ltd. Quinolone derivatives
CN108349968A (zh) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 抗菌治疗剂和预防剂
JP2018528260A (ja) * 2015-07-28 2018-09-27 ビオーム バイオサイエンシズ プライベート リミティド 抗菌性治療薬及び予防薬
JP2020050676A (ja) * 2015-07-28 2020-04-02 ビオーム セラピューティクス リミティド 抗菌性治療薬及び予防薬
JP2020508999A (ja) * 2016-11-02 2020-03-26 アクトシオナーノエ オブシェストヴォ“タツフィムファルムプレパラティ” シプロフロキサシン誘導体系抗菌薬
US10759810B2 (en) 2016-11-02 2020-09-01 Ao “Tatkhimfarmpreparaty” Antibacterial agents based on ciprofloxacin derivatives
RU2757741C1 (ru) * 2021-03-01 2021-10-21 Федеральное государственное бюджетное учреждение науки Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук (ИХБФМ СО РАН) Производное ципрофлоксацина, обладающее антибактериальной активностью в отношении антибиотикоустойчивых штаммов микроорганизмов
US11945800B1 (en) 2023-09-21 2024-04-02 King Faisal University 1-cyclopropyl-6-fluoro-4-oxo-7-(4-((5-oxo-2-phenyl-4-(quinolin-2-ylmethylene)-4,5-dihydro-1H-imidazol-1-yl)methyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid as an anti-inflammatory and anticancer compound

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