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WO2012079164A1 - Activateurs des protéases cylindriques - Google Patents

Activateurs des protéases cylindriques Download PDF

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Publication number
WO2012079164A1
WO2012079164A1 PCT/CA2011/001406 CA2011001406W WO2012079164A1 WO 2012079164 A1 WO2012079164 A1 WO 2012079164A1 CA 2011001406 W CA2011001406 W CA 2011001406W WO 2012079164 A1 WO2012079164 A1 WO 2012079164A1
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substituted
unsubstituted
compound
alkyl
cycloalkyl
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Inventor
Walid A. Houry
Elisa Leung
Robert Batey
Michele Cossette
Jordan Goodreid
Alessandro Datti
Jun Liu
Alan Jay Nhieu
Scott D. Gray-Owen
Emil Friedrich Fai
Bryan Timothy Eger
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University of Toronto
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University of Toronto
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/55—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/76—Sulfur atoms attached to a second hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention is directed to activators of cylindrical proteases, particularly ClpP, and the role thereof in the diagnosis and treatment of bacterial infections.
  • ClpP caseinolytic protease P
  • ADEPs acyldepsipeptides
  • ClpP a target of the ADEPs, is a tetradecameric serine protease comprised of two stacked heptameric rings which, in Escherichia coli, can form complexes with the AAA+ ATPase chaperones ClpX or ClpA.
  • ClpX and ClpA are hexameric chaperones that bind on one or both ends of ClpP.
  • the chaperones bind to target proteins, unfold them, and then thread them into the ClpP proteolytic chamber through axial pores lined by axial loops for degradation. These activities require ATP.
  • ClpP alone can efficiently degrade small peptides of up to about 30 amino acids and can also degrade unstructured proteins albeit with much lower efficiency when compared to ClpXP or ClpAP.
  • ADEPs enhance the efficiency of ClpP- dependent degradation of unstructured proteins by opening up the ClpP axial pores. 0005
  • ADEPs enhance the efficiency of ClpP- dependent degradation of unstructured proteins by opening up the ClpP axial pores.
  • An embodiment of the present invention is directed to activators of cylindrical proteases, particularly ClpP, in the diagnosis and treatment of bacterial infections.
  • An embodiment of the present invention is directed to a compound of formulae (I) or (II).
  • R 1 and R 2 are H, CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or
  • R 3 is H, CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 2 -C 8 cycloalkyl, a substituted or unsubstituted aryl, or a substituted or
  • R 4 , R 5 and R 6 are H, F, CI, Br, I, N0 2 , CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl or a substituted or unsubstituted C 2 -C 8 cycloalkyl, CF 3 , CN, a substituted or unsubstituted aryl, COOH, COOR 7 , CONR 7 2 , COR 7 , OR 7 , NR 7 2 , or SR 7 , wherein R 7 is H, a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 2 -C 8 cycloalkyl or a substituted or unsubstituted aromatic group;
  • X and Y are CH or N;
  • V is H/H, O, or H/R 8 , wherein R 8 is CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 2 -C 8 cycloalkyl, or substituted or a unsubstituted aryl;
  • Ar is a substituted or unsubstituted aromatic, a substituted or unsubstituted fused
  • n 0, 1 , 2, 3;
  • formulae (I) or (II) do not include ACPI or ACP2.
  • C 2 -C 8 alkyl group is a substituted or unsubstituted ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl or octyl.
  • Yet another embodiment is directed to wherein the C 2 -C 8 cycloalkyl group or the C 2 -C 8 spiro cycloalkyl is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • substituted or unsubstituted aryl group is a substituted or unsubstituted phenyl.
  • substituted or unsubstituted aromtic group comprises a substituted or unsubstituted phenyl.
  • substituted or unsubstituted aromatic group is substituted with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, COOR 10 , CONR I0 2 , COR 10 , OR 10 , or NR 10 2 wherein R 10 is H, CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, or a substituted or unsubstituted aryl.
  • substituted or unsubstituted fused aromatic group is a substituted or unsubstituted naphthalene or a substituted or unsubstituted indene.
  • substituted or unsubstituted heteroaromatic group is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, substituted or unsubstituted triazine, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole or
  • fused heteroaromatic group comprises substituted or unsubstituted indole, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiphene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzthiazole, substituted or unsubstituted benzoxazole or substituted or unsubstituted benzpyrazole.
  • R 1 is H, CH 3 , a substituted or unsubstituted Ci-Cg alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic, a substituted or unsubstituted fused aromatic, a substituted or unsubstituted heteroaromatic, or a substituted or unsubstituted fused heteroaromatic;
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are H, CH 3 , a substituted or unsubstituted Ci-Cg alkyl, a
  • substituted or unsubstituted C3-C8 cycloalkyl a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic, a substituted or unsubstituted fused aromatic, a substituted or unsubstituted heteroaromatic, a substituted or unsubstituted fused heteroaromatic;
  • X is CH and N
  • substituted or unsubstituted Ci-Cg alkyl group is a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
  • substituted or unsubstituted C3-C8 cycloalkyl group or the C 2 -Cg spiro cycloalkyl is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • substituted or unsubstituted alkenyl is vinyl, propenyl or dihalovinyl.
  • substituted aromatic is substituted with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, COOR ] 0 , CONR 10 2 , COR 10 , OR 10 , or NR 10 2 wherein R 10 is H, CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted aryl.
  • Yet another embodiment is directed to wherein the fused aromatic group is a substituted or unsubstituted naphthalene or a substituted or unsubstituted indene.
  • substituted or unsubstituted heteroaromatic group is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, substituted or unsubstituted triazine, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole or substituted or unsubstituted tetrazole.
  • fused heteroaromatic group comprises substituted or unsubstituted indole, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiphene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzthiazole, substituted or unsubstituted benzoxazole or substituted or unsubstituted benzpyrazole.
  • R 1 is CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl or a substituted or unsubstituted C 3 - C cycloalkyl;
  • R 2 and R 3 are H, a substituted or unsubstituted alkyl, a substituted or unsubstituted
  • cycloalkyl a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic, a substituted or unsubstituted fused aromatic, a substituted or unsubstituted heteroaromatic, or a substituted or unsubstituted fused heteroaromatic;
  • formulae (IV) does not include ACP4 or ACP5.
  • substituted or unsubstituted Ci-C 8 alkyl group is a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, or butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
  • substituted or unsubstituted C 3 -C 8 cycloalkyl group is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • substituted or unsubstituted alkyl is a substituted or unsubstituted methyl, ethyl, propyl, isopropyl or butyl.
  • substituted or unsubstituted cycloalkyl is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • substituted or unsubstituted alkenyl group is vinyl, propenyl or dihalovinyl.
  • substituted aromatic is substituted with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, COOR 10 , CONR 10 2 , COR 10 , OR 10 , or NR 10 2 wherein R 10 is H, CH 3 , a substituted or unsubstituted C 2 -C 8 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, or a substituted or unsubstituted aryl.
  • Yet another embodiment is directed to wherein the fused aromatic group is a substituted or unsubstituted naphthalene or a substituted or unsubstituted indene.
  • substituted or unsubstituted heteroaromatic group is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, substituted or unsubstituted triazine, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole or substituted or unsubstituted tetrazole.
  • fused heteroaromatic group comprises substituted or unsubstituted indole, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiphene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzthiazole, substituted or unsubstituted benzoxazole or substituted or unsubstituted benzpyrazole.
  • Yet another embodiment is directed to an antibacterial compound selected from the group consisting of any of the preceding compounds and pharmaceutically acceptable salts thereof.
  • Yet another embodiment is directed to an antibacterial compound selected from the group consisting of ACPI, ACP2, ACP3, ACP4, ACP5 and pharmaceutically acceptable salts thereof.
  • Yet another embodiment is directed to the antibacterial comprising ACPI, ACP3, ACP4, ACP5, more preferably, ACPI and ACP3, and pharmaceutically acceptable salts thereof.
  • 0040 Yet another embodiment is directed to a cylindrical protease (preferably ClpP) activator for use as an antibacterial compound.
  • Yet another embodiment is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the preceding compounds or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipients, diluents and/or carriers.
  • FIG. 1 shows results of the high-throughput compound screen for embodiments of the present invention.
  • A shows compounds that were screened to find activators of E. coli ClpP.
  • B-score values were calculated for each compound from the increase in fluorescence intensity after a six-hour incubation of casein-FITC with ClpP and the applicable compound. Compounds confirmed as hits, designated ACPI through ACP5, are indicated by the arrows.
  • B shows chemical structures of embodiments of the present invention.
  • FIG. 2 shows the relative degradation index of embodiments of the present invention.
  • A Shown is the effect of compound concentration on casein-FITC degradation by ClpP after six-hour incubation. Data are the average of three repeats. Error bars represent standard deviations.
  • B Comparison of the relative degradation index at 25 ⁇ compound (RD25) values for the ACP compounds. Data shown represent the average of three repeats. SD is standard deviation.
  • FIG. 3 shows the chemical optimization of embodiments of the present invention.
  • A General chemical structure of embodiments of the present invention.
  • B A schematic of the chemical reaction used to synthesize embodiments using PyBOP mediated amide bond formation between 2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)thio)propanoic acid and primary amines.
  • C RD25 values of embodiments of the present invention.
  • D Shown is the degradation of unlabeled casein by compound-activated ClpP followed on SDS-PAGE gels.
  • FIG. 4 shows the determination of binding affinity to ClpP of embodiments of the present invention.
  • A ITC binding curves for interaction of ClpP and embodiments of the present invention. Results for the fit of the data to one set of an identical independent binding site model is given in the table. Numbers in parentheses refer to standard deviations from the fit.
  • B Cooperativity of binding of various embodiments to ClpP was determined by measuring the change in casein degradation rate by compound-activated ClpP as a function of compound concentration.
  • FIG. 5 shows the effect of embodiments on ClpP oligomeric stability.
  • Embodiments of the present invention (at 100 ⁇ ) promote the tetradecamerization of ⁇ 31.
  • the table lists the sedimentation coefficients, frictional ratios, and molecular weights corresponding to the various peaks.
  • the peaks of the different curves correspond to the following MW: 1 , 134 kDa; 2, 140 kDa; 3, 277 kDa; 4, 145 kDa; 5, 297 kDa; 6, 145 kDa; 7, 282 kDa; 8, 148 kDa; 9, 303 kDa.
  • B provides sedimentation equilibrium profiles and the corresponding distribution of residuals for 51uM ClpP in the absence of compound (top), or in the presence of lOOuM ACPI a (middle) or l OOuM ACPlb (bottom).
  • FIG. 6 shows possible ACP binding sites.
  • A Shown is the inhibition of ClpXP- mediated GFP-ssrA degradation by ACPs and ADEPs added at 100 ⁇ monitored on SDS- PAGE gels. ClpP was pre-incubated with compound before the addition of ClpX.
  • B Surface model of ClpP is shown on the top left. Four neighboring subunits are colored in alternating blue and green. The H pockets are colored in purple while the C pockets are colored in yellow. The bottom left panel shows a close up view of the predicted compound binding conformations in the two ClpP pockets. Various embodiments are overlaid in the binding pockets. ClpP is shown as a surface model and the compounds are shown as stick models.
  • C, N, O, S, F, CI, Br, and H in the compounds are colored in gray, blue, red, yellow, cyan, green, purple and white, respectively.
  • the ClpP surface is colored according to the electrostatic potential (red is ⁇ -4 kT/e and blue is > 4 kT/e) calculated using DelPhi.
  • stick models of ACPI docked into the H and C pockets of ClpP drawn as ribbons colored by chain.
  • C, N, O, S, F, and H are colored in orange, blue, red, yellow, cyan and white, respectively. All molecular graphics figures were prepared using the program PyMOL.
  • C Effect of mutations in the H and C pockets on ClpP activation by compounds measured using RD25. Data shown represent the average of three repeats and the standard deviations are represented as error bars.
  • FIG. 7 shows the confirmation of ClpP activation by the hits identified in the high- throughput screen.
  • the disappearance of unlabeled casein due to degradation by compound- activated ClpP was followed over time on SDS-PAGE gels, which were then stained with Coomassie Brilliant Blue.
  • FIG. 8 shows the degradation of alternative substrates by compound-activated ClpP. Shown is the degradation of the indicated substrates by compound-activated ClpP followed on SDS-PAGE gels for 6 hours.
  • FIG. 9 shows the chemical structures of ADEP1A and ADEP1B.
  • FIG. 10 shows the formation of intermediates during casein degradation by embodiment- activated ClpP. Intermediate species, indicated by the parenthesis, resulting from casein degradation were resolved on 18% percent SDS-PAGE gels.
  • FIG. 11 shows Surface Plasmon Resonance ("SPR") analysis for the binding of ClpP with different activators.
  • Graphs on the left represent the stacked sensorgrams from SPR experiments of embodiments at various concentrations injected over a biosensor chip surface immobilized with ClpP.
  • Graphs on the right depict the binding curves constructed with the steady state data fit to a one-site Langmuir binding model. The K d obtained by the fits are listed in the table at the bottom.
  • FIG. 12 shows the inhibition of ClpXP-mediated GFP-ssrA degradation by ACPs. 100 ⁇ of ACPI -5 inhibited or reduced GFP-SsrA degradation by ClpXP as monitored on SDS- PAGE gels.
  • FIG. 13 shows binding conformations of an embodiment of the present invention in the H and C pockets of ClpP.
  • ClpP and compounds are shown as surface and stick models, respectively.
  • the color scheme is the same as that used in Fig. 6B.
  • FIG. 14 shows the effect of mutations in the H and C pockets on ClpP activity.
  • Peptidase assays comparing the peptide hydrolysis activities of various E. coli ClpP mutants against the Suc-LY-AMC peptide. Mutations were made in the H pocket, C pocket, or in combination. The color scheme is the same as that for FIG. 6C. Values were normalized to the wild type ClpP peptide hydrolysis rate. Mutants with peptidase activity less than 70% of WT are grouped on the right. Data shown represent the average of three repeats and the standard deviations are represented by the error bars.
  • FIG. 15 shows the activity of embodiments, measured using RD25, of the present invention.
  • Table 1 shows the minimum bactericidal concentration of embodiments of the present invention.
  • Table 2 shows RD25 values for ClpP Activation by ACPI Analogs.
  • Table 3 shows in vitro and in vivo activity data of embodiments of the present invention.
  • Table SI shows ClpP degradation assays with alternative substrates.
  • Table S2 shows minimum bactericidal concentration of compounds.
  • Table S3 shows ZINC ID corresponding to ACP4 chiral isomers.
  • Table S4 shows ZINC ID corresponding to ACP5 chiral isomers.
  • FIG. 16 shows a crystal structure of an embodiment of the present invention (Compound No. 93) bound to an active site of ClpP.
  • FIG. 17 shows loss of clpP confers resistance to ADEP and ACP in N. meningitidis H44/76 and E. coli MC4100 (see also FIG. 3).
  • A PCR verification of clpP insertional mutagenesis N. meningitidis H44/76. Genomic DNA recovered from wild type (W) or erythromycin-resistant N. meningitidis H44/76 transformants (A and B, representing two replicate samples) were used as template for PCR with the indicated primer pairs. The schematic depicts relative location of oligonucleotide primer sequences on the genome of the clpP mutant bacteria.
  • B Fresh overnight cultures of N.
  • meningitidis H44/76 were spread onto the surface of standard growth media, and filter discs impregnated with 256 ⁇ g/mL of ADEP 1 A or ADEP IB were laid on the surface. Zones of clearing on plates cultured with WT meningococci reflect inhibition of bacterial growth, whereas no inhibitory effect of either compound was apparent on plates cultured with the meningococcal clpP mutant.
  • C The chemical structures of ADEP 1 A and ADEP IB.
  • D Upper panel shows the growth curves for WT and AclpP E. coli MC4100 in the presence of 20 uM CCCP or 20 uM CCCP + 128 ug/mL ACPIB in LB at 30°C. The curves shown represent the average of 3 cultures. The lower panel shows OD600 at 900 minutes for the two strains.
  • FIG. 18 shows binding of ClpP to ADEP 1 A, ADEP IB, and ACPlb (see also FIG. 4).
  • A ITC binding curves for ClpP-ADEPlA, ADEP IB, or ACPlb interaction. Results for the fit of the data to a one set of identical independent binding site model is given in the table. The number of binding sites, n, were fixed in the fit to the indicated whole number. Numbers in parentheses refer to standard deviations. %2/DoF refers to chi-squared divided by the degrees of freedom and indicates the quality of the fit (see also FIG. 4A).
  • B Same as A, but n was fixed to 14.
  • alkyl includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group.
  • Alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on, any of which may be substituted or unsubstituted.
  • alkenyl includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond. Unless indicated otherwise by the prefix that indicates the number of carbon members, alkenyls include, but are not limited to, ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), isopropenyl (or 1 -methylvinyl), but-l -enyl, but-2- enyl, butadienyls, pentenyls, hexa-2,4-dienyl, dihalovinyl, and so on, any of which may be substituted or unsubstituted.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on, any of which may be substituted or unsubstituted.
  • heterocyclyl is an aromatic, saturated, or partially saturated single or fused ring system that comprises carbon atoms wherein the heteroatoms may be nitrogen, sulfur and oxygen.
  • heterocyclic groups include, but are not limited to, thiazoylyl, thienyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and
  • heteroaromatics and fused heteroaromatics include, but are not limited to, naphthalene, indene, quinoline, isoquinoline, benzimidazole, benzthiazole, benzoxazole, furan, pyrrole, pyridine, pyrimidine, pyrazine, triazine, thiophene, furan, oxazole, thiazole, imidazole, any of which may be substituted or unsubstituted.
  • aryl or “aromatic”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as, for example, phenyl, naphthyl or indenyl, any of which may be optionally substituted. Unless indicated otherwise, the terms “heteroaryl” or “heteroaromatic” refer to those heterocycles that are aromatic in nature.
  • Substituted aromatics can include aromatics mono- or polysubstituted at the ortho, meta or para positions by substituents that include, but are not limited to, a halo, CF 3 , CN, N0 2 , alkyl, aryl, COOH, a fused aromatic, a heteroaromatic, a fused heteroaromatic, COOR, CONR 2 , COR, OR, NR 2 , where R may be H, CH 3 , C 2 -C 8 alkyl/cycloalkyl, phenyl, or aryl, any of which may be substituted or unsubstituted.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • an isotopically labeled compound such as an isotopically labeled compounds that may be used as a probe in detection and/or imaging techniques.
  • an isotopically labeled compound such as a deuterium and/or tritium labeled compound that may be used in reaction kinetic studies.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the desired compound.
  • the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but that converts to the specified compound in vivo after administration to a subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described standard references and are known in pharmaceutical manufacturing.
  • Reference to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
  • Salt also comprises the hydrates and solvent addition forms that compounds of the present invention are able to form. Examples of such forms are hydrates, alcoholates, and generally solvates.
  • Subject refers to eukaryotic organisms and it includes mammals such as human beings and animals (e.g., dogs, cats, horses, rats, rabbits, mice, non-human primates, etc.) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition.
  • the patient or subject is a human being.
  • “Pharmaceutically acceptable” means those active agents, salts and esters, and excipients which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Composition includes a product comprising the specified ingredients in effective amounts, as well as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts.
  • ClpP is a cylindrical tetradecameric serine protease whose activity is regulated by the unfoldase ATP-dependent chaperones of the AAA+ superfamily.
  • the chaperones act to select substrate proteins, unfold them, and then thread them into the ClpP cylinder for degradation.
  • ClpP on its own can only degrade small peptides.
  • Embodiments of the present invention are directed to cylindrical protease activators. Further embodiments of the present invention are directed to cylindrical protease activators having antibacterial properties based on the activation and dysregulation of ClpP activity. Preferred embodiments include ACPI to ACP5 as antibacterial compounds.
  • Embodiments of the present invention are directed to compounds termed Activators of Self-Compartmentalizing Proteases ("ACPs").
  • ACPs Activators of Self-Compartmentalizing Proteases
  • the chemical structures of ACPs identified herein differ significantly from the structures of the previously identified ADEPs.
  • ADEPs Activators of Self-Compartmentalizing Proteases
  • a number of ACPs have been identified including, but not limited to ACPI (Nl [2(phenylthio)ethyl]2methyl2 ⁇ [5(trifluoromethyl)2pyridyl]sulfonyl ⁇ propanamide), ACP2
  • analogs thereof were developed through chemical optimization of the identified ACPs, including but not limited to ACPI, which resulted in analogs having the desired bioactivity.
  • 0090 ClpP was used as a target in a high-throughput screen to identify compounds which activate ClpP so as to allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones.
  • the cylindrical protease activators of the present invention may stabilize the ClpP double ring structure.
  • the ACPs represent new classes of compounds that can activate ClpP and can be potential antibiotics. It has been found that the compounds of this invention and compositions containing these compounds have antibacterial activities against pathogenic microorganisms, particularly bacterial strains.
  • the present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of at least one embodiment of the present invention and/or derivative thereof.
  • the present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of at least one embodiment of the present invention and/or derivative thereof.
  • the invention also features a pharmaceutical composition for treating or preventing bacterial infection in a subject, comprising a therapeutically effective amount of at least one antibacterial agent selected from the embodiments of the present invention, including but not limited to enantiomers, diastereomers, racemates, tautomers, hydrates, solvates thereof, pharmaceutically acceptable salts, amides and esters thereof.
  • the invention features a pharmaceutical composition for inhibiting bacterial activity or infection in a subject, comprising a therapeutically effective amount of at least one antibacterial agent selected from the embodiments of the present invention, including but not limited to enantiomers, diastereomers, racemates, tautomers, hydrates, solvates thereof, pharmaceutically acceptable salts, amides and esters thereof.
  • FIG. IB further embodiments of the present invention are directed to compounds representing four different structural classes that can activate ClpP and that have bactericidal properties.
  • ACP4 and ACP5 these compounds have no apparent structural similarities to each other or to previously identified ADEPs.
  • the optimization of ACPI resulted in compounds that had in vitro ClpP activation properties similar and even exceeding that of the known ADEPs (see Fig. 3C).
  • these additional compounds have good bactericidal properties and further chemical modification and optimization could unlock their fullest potential, both by improving ClpP affinity and activation as well as by improving compound solubility and cell permeability.
  • Embodiments of the present invention may be directed to analogs of ACPI to ACP5.
  • Preferred embodiments of the present invention may be directed to analogs of ACPI .
  • the preferred embodiments of the ACPI analogs are directed to compounds of formulae (I) or (II).
  • R 1 and R 2 may be H, CH 3 , a C 2 -C 8 alkyl / cycloalkyl (preferably, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a C 2 -C 8 spiro
  • cycloalkyl i.e., where R / R are linked together in a ring
  • R 3 may be H, CH 3 , a C 2 -C 8 alkyl / cycloalkyl (preferably, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), an aryl (preferably, phenyl), or
  • a fused ring i.e., where R may be linked together with R / R , V, Z or Ar to form a ring
  • R 4 , R 5 and R 6 may be H, a halo, N0 2 , CH 3 , a C 2 -C 8 alkyl / cycloalkyl (preferably, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), CF 3 , CN, an aryl (preferably, phenyl), COOH, COOR 7 , CONR 7 2 , COR 7 , OR 7 , NR 7 2 , or
  • R may be H, C 2 -C 8 alkyl / cycloalkyl, phenyl or substituted aromatic;
  • X and Y may be CH or N;
  • V may be H/H, O, or H/R 8 , wherein R 8 may be CH 3 , a C 2 -C 8 alkyl / cycloalkyl [preferably, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl], or an aryl [preferably, phenyl]);
  • Ar may be phenyl, a substituted aromatic, preferably, with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, a fused aromatic (preferably, naphthalene, indene), a heteroaromatic (preferably, pyridine, pyrimidine, pyrazine, triazine, thiophene, furan, oxazole, thiazole, imidazole), or a fused heteroaromatic
  • Embodiments of the present invention may be directed to analogs of ACP3.
  • the preferred embodiments of the ACP3 analogs are directed to compounds of formulae (III).
  • R 1 may be H, CH 3 , other C 2 -C 8 alkyl / cycloalkyl (preferably, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl or substituted alkenyl (e.g., vinyl, propenyl, dihalovinyl), phenyl, substituted aromatic (preferably, with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, COOR 8 , CONR 8 2 , COR 8 , OR 8 , NR 8 2 , wherein R 8 may be H, methyl, C 2 -C 8 alkyl / cycloalkyl, phenyl or substituted aromatic]), a fused aromatic (e.g., naphthalene, indene), a hetero
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be H, CH 3 , a C 2 -C 8 alkyl / cycloalkyl (preferably, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl or substituted alkenyl (e.g., vinyl, propenyl, dihalovinyl), phenyl, a substituted aromatic (preferably, with ortho, meta or para F, CI, Br, I, CF 3 , CN, N0 2 , alkyl, aryl, COOH, COOR 9 , CONR 9 2 , COR 9 , OR 9 , NR 9 2 , wherein R 9 may be H, methyl, C 2 -C 8 alkyl / cycloalkyl, phenyl or substituted aromatic]), a fuse
  • X may be CH and N.
  • Embodiments of the present invention may be directed to analogs of ACP4 and ACP5.
  • the preferred embodiments of the ACP4/5 analogs are directed to compounds of formulae (IV):
  • R 1 may be CH 3 or a C 2 -C 8 alkyl / cycloalkyl (preferably, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).
  • R 2 and R 3 may be H, alkyl / cycloalkyl (preferably, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl or substituted alkenyl (e.g., vinyl, propenyl, dihalovinyl), phenyl, substituted aromatic
  • R may be H, methyl, a C 2 -C 8 alkyl / cycloalkyl, phenyl or substituted aromatic, fused aromatic (preferably, naphthalene or indene), a heteroaromatic (preferably, pyridine, pyrimidine, pyrazine, triazine, thiophene, furan, oxazole, thiazole, imidazole), a fused heteroaromatic (preferably, quinoline, isoquinoline, benzimidazole, benzthiazole, benzoxazole).
  • a high-throughput screening assay was developed with a fluorescence-based readout.
  • the assay employed fluorescein isothiocyanate-labeled casein (casein-FITC) as the proteolytic target of the E. coli ClpP.
  • casein-FITC fluorescein isothiocyanate-labeled casein
  • FITC fluorescence is quenched; protease-catalyzed hydrolysis of casein-FITC relieves this quenching, yielding highly fluorescent dye-labeled peptides.
  • the high-throughput screening assay may be used to select compounds that resulted in increased fluorescence upon incubation of casein-FITC with ClpP.
  • 00108 ⁇ is the change in fluorescence after 6 hours of starting the reaction, measured using 485 nm excitation and 535 nm emission, which primarily detects the signal from casein-FITC.
  • each reaction consisted of 3.6 ⁇ ClpP and a specified amount of compound in buffer A (25 mM TrisHCl, pH 7.5, and 100 mM KC1). The reactions were pre- incubated for 10 minutes at 37°C before 4.5 ⁇ casein-FITC and 15.5 ⁇ unlabelled casein (to ensure that the substrate is in excess) were added. ClpAP-dependent degradation of the same casein-FITC substrate was used as a control.
  • Each ClpAP reaction contained 3.6 ⁇ ClpP, 3 ⁇ ClpA and 0.3 mM ATP in buffer B (25 mM HEPES pH 7.5, 20 mM MgCl 2 , 30 mM C1, 0.03% Tween 20, and 10% glycerol), and an ATP-regenerating system (13 units/mL of creatine kinase and 16 mM creatine phosphate). Reactions were incubated at 37°C and the fluorescence (485 nm excitation, 535 nm emission) was monitored every 15 minutes for 6 hours on a PHERAStar detection system.
  • Casein-FITC degradation by compound-activated ClpP after 6 hours at 37°C was compared to the ClpAP-dependent casein-FITC degradation after 6 hours at 37°C, using equation (1).
  • the number next to RD refers to the final concentration, in ⁇ , of the compound in the reaction mixture.
  • RD25 refers to the RD value measured using 25 ⁇ of final compound concentration.
  • E. coli ClpAP is used as a benchmark for maximum ClpP proteolytic activity.
  • ACPI satisfies Lipinski's rule of five and has a topological polar surface area of 75.6, calculated molar refractivity of 10.4, and Clog P of 3.98.
  • the structure of ACPI consists of a central ⁇ -amido sulfone core appended with a western electron deficient pyridyl ring and an eastern hydrophobic tail incorporating a phenylthioether group (Fig. IB and 3 A).
  • the natural synthetic disconnection point chosen for the synthesis of analogs of ACPI was the amide linkage (Fig 3A).
  • Analogs were synthesized using a late-stage amide-bond forming reaction between the eastern amine and the western ⁇ -sulfonyl carboxylic acid (Fig 3B) using well-known synthetic protocols and, subsequently, evaluated by measuring their RD25 values.
  • ADEP1 factor A and B isolated from Streptomyces hawaiiensis as a reference.
  • ADEPIA has a higher ClpP activation activity than ADEP1B (Fig. 3C).
  • a screen of analogs identified a preferred embodiment, ACPlb (Fig. IB) that had an RD25 value slightly higher than that of ADEPIA (Fig. 3C).
  • ACP la that had a lower RD25 value than that of ACPlb, but comparable to that of ADEP1B (Fig. 3C)
  • ACPla incorporates a sulfur to methylene substitution in the eastern tail
  • ACPlb has an ortho-ch oro substituent in the arylthioether ring (Fig. IB).
  • ACPlb had the lowest MBC value against H. influenzae compared to ACPI and ACPla; the MBC of ACPlb was similar to that of ADEPIA (see Table 1). ACPlb also had an improved MBC value against N. meningitidis compared to ACPI and ACPla, but not ADEPIA (see Table 1). These results suggest that the optimization efforts improved the antibacterial properties of ACPI . Table 1. Minimum bactericidal concentration of compounds.
  • ADEPs have been found to bind in a hydrophobic pocket (the "H pocket") on ClpP apical surface in which the IGF loop of the ClpX/ClpA ATPases also binds.
  • H pocket hydrophobic pocket
  • the presence of the ADEPs inhibited or reduced the ClpXP/ClpAP-mediated degradation of GFP-ssrA by interfering with the binding of ClpX/ClpA to ClpP.
  • Fig. 6 A and 12 a similar effect was also seen for embodiments of the present invention suggesting that these compounds may bind to or allosterically modulate the H pocket of ClpP.
  • the H pocket is composed of residues V42, F44, L62, Y74, Y76, 1104, F126, L203, and R206 from one subunit, and L37 and F96 from the neighboring subunit.
  • the C pocket comprises residues Y90, M94, Q95, D 100, VI 01, and HI 70 of one subunit and residues H205, N207 of the neighboring subunit.
  • H and C pockets are separated by residues at the very C-terminus of ClpP, corresponding to amino acids 203 - 207 (using Swiss-Prot numbering). While ADEPs co-crystallized with ClpP were found bound to the H pocket, all the ACP compounds were well docked to both the H and C pockets (Fig. S7), and their docking scores differed little between the two pockets (Table S5).
  • the identified ACP compounds may share a similar mechanism of ClpP activation as the ADEPs, including, but not limited to stabilizing ClpP and promoting the formation of the double ring structure.
  • the embodiments may confer on ClpP similar degradation patterns (Fig. 10).
  • the embodiments of the present invention may prevent the binding of ClpP to its associated unfoldase (Figs. 6A and 12), and may, at the same time, activate nonspecific proteolysis.
  • ClpA pET9a ClpP and pET9a ClpA(M169T) were used for overexpressing the respective E. coli proteins.
  • the M169T mutation in ClpA removes an internal translation initiation site.
  • ClpA(M169T) is referred to as ClpA.
  • pHFOlO plasmid encoding ⁇ 6 - ⁇ was used to produce and the protein was purified according to protocols described elsewhere.
  • ADEP1A and ADEP1B were purified to at least 95% homogeneity from the fermentation culture of S. hawaiiensis.
  • the libraries employed for the screening campaigns were composed of experimental bioactives, pharmacologically-active chemicals and natural products, off-patent marketed drugs, and small molecules with drug-like properties.
  • Samples were obtained from the following, commercially-available collections: LOPAC 1280TM (Sigma, USA, 1280 samples), Prestwick Chemical library® (Prestwick Chemical, France, 1 120 samples), SPECTRUM collection (MicroSource, USA, 2000 samples), Maybridge Screening collection (Maybridge-Thermo Fisher Scientific, UK, 50,000 samples), and Chembridge DIVERSetTM (ChemBridge Corp, USA, 10,000 samples).
  • samples stored in 384-well plates as 1 mM or 5 mM solutions in 100% DMSO were transferred to assay plates in a fixed volume of 200 nL by a pin-tool (V&P Scientific, USA). Screens were conducted using a fully automated procedure run on a DIM4 fiipmover platform (Thermo Electron Corp) equipped with a Biomek FX liquid handler (Beckman, USA) and a PHERAStar detection system (BMG Labtech, Germany).
  • the reaction for the screening assay contained 20 ⁇ compound, 3.6 ⁇ ClpP, and 4.5 ⁇ casein-FITC in buffer A (25 mM TrisHCl, pH 7.5, and 100 mM KCl) at 37°C.
  • each reaction consisted of 3.6 ⁇ ClpP and a specified amount of the applicable the applicable compound in buffer A. The reactions were pre- incubated for 10 minutes at 37 ° C before 4.5 ⁇ casein-FITC and 15 ⁇ unlabelled casein were added. ClpAP-dependent degradation of the same casein-FITC substrate was used as a positive control.
  • Each ClpAP reaction contained 3.6 ⁇ ClpP, 3 ⁇ ClpA and 0.3 mM ATP in buffer B (25 mM HEPES pH 7.5, 20 mM MgCl 2 , 30 mM KC1, 0.03% Tween 20, and 10% glycerol), and an ATP-regenerating system (13 units/mL of creatine kinase and 16 mM creatine phosphate). Reactions were incubated at 37°C and the fluorescence (485 nm excitation, 535 nm emission) was monitored every 15 minutes for 6 hours on a PHERAStar detection system. Casein-FITC degradation by compound-activated ClpP after 6 hours at 37°C was compared to the ClpAP- dependent casein-FITC degradation after 6 hours at 37°C, using equation (1) set out herein.
  • 00132 Peptidase activity of ClpP was measured by the ability of ClpP to cleave the dipeptide Suc-LY-AMC.
  • Each reaction contained 1 ⁇ ClpP in buffer D (50 mM TrisHCl, pH 8, 200 mM KC1, and 1 mM DTT).
  • ClpP was incubated for 3 minutes at 37°C before Suc-LY-AMC was added to a final concentration 0.5 mM. Fluorescence (350 nm excitation, 460 nm emission) of the released AMC was detected on the PHERAStar system.
  • each reaction consisted of 3.6 ⁇ ClpP and specified amount of the identified compound in buffer A. The reactions were pre-incubated for 10 minutes at 37 ° C before 4.5 ⁇ casein-FITC was added. Reactions were incubated at 37°C and the fluorescence (485 nm excitation, 535 nm emission) was monitored every 3 seconds for 5 minutes on an EnSpire Multilabel Plate Reader (PerkinElmerTM).
  • SPR Surface Plasmon Resonance
  • Binding experiments were performed at 20 in running buffer E (20 raM TrisHCl, pH 7.5, 100 mM KC1, 3 mM EDTA, 0.005% P20 surfactant, and 5% DMSO).
  • An association phase of a 60 or 120 seconds injection of compound was followed by a dissociation phase of 60 or 120 seconds of running buffer flow before the chip and sample loop were washed at high flow rate.
  • the surface was regenerated between injections with a one minute pulse of 10% DMSO in running buffer E.
  • the steady state responses were plotted versus the corresponding analyte concentrations and fit to one-site Langmuir binding models using BiaEvaluation 4.1 software (GE Healthcare).
  • ITC Isothermal Titration Calorimetry
  • Sedimentation velocity analytical ultracentrifugation was carried out at the Ultracentrifugation Service Facility at the Department of Biochemistry, University of Toronto. 1 mg/rriL ClpP was exchanged into buffer B containing 100 ⁇ of the applicable compound by dialysis. Samples were spun at 45,500 g at 4°C in a Beckman Optima Model XL-A analytical ultracentrifuge equipped with an An-60 Ti rotor. 00138 The density and viscosity of buffer and the partial specific volumes of proteins used were calculated using SEDNTERP. The sedimentation data were fit to a continuous distribution model c(s) using SEDFIT. The observed sedimentation coefficients obtained from the fitting were corrected to the density and viscosity of water at 20°C to obtain s 20i w .
  • MBC minimum bactericidal concentrations
  • H. influenzae, N. gonorrhoeae, N. meningitidis, and S. pneumoniae were incubated in the presence of 5% C0 2 . 2 i of culture from the incubations were then plated onto compound-free agar plates (H. influenzae, N. gonorrhoeae, N. meningitidis for 18 to 20 hours; remaining strains for 12-16 hours) to determine the bactericidal activity.
  • H. influenzae was grown on chocolate agar; N gonorrhoeae on GC agar base; N.
  • Cultures were then diluted 10 fold and 5 ⁇ , were used to inoculate 100 of a two-fold dilution series of compounds in the range of 1 ⁇ g/mL to 256 ⁇ g/mL in 7H9 broth supplemented with OADC and 0.2% glycerol in the presence or absence of 12.5 ⁇ g/mL polymyxin B.
  • Polymyxin B is known to enhance mycobacterial permeability to hydrophobic compounds.
  • the solvent control, DMSO at 2% or less showed no inhibitory effects on M. smegmatis growth. Plates were incubated in a C0 2 incubator for 8 days. Following incubation, dilutions of sample aliquots were spread on Middlebrook 7H1 1 plates (Difco, BD biosciences) supplemented with 2% OADC and 0.5% glycerol for determination of bacterial viability.
  • ClpP used in the docking procedure was that of E. coli ClpP (PDB code lyg6).
  • a dimer of the neighboring chains A and G in the PDB entry were extracted from one heptameric ring of ClpP and used for docking procedures.
  • the DOCK6.3 package was used to dock the flexible conformations of the five compounds into the structure of ClpP, which was kept rigid. For each compound the 'anchor and grow' method was used with default options.
  • the SPHGEN algorithm was used to identify ligand binding pockets on the surface of the ClpP dimer facing ClpX. Two pockets were predicted: one largely hydrophobic pocket corresponding to the ClpX IGF loop binding cleft was designated as the H pocket. The second pocket, located nearby, was designated as the C pocket. Docking calculations were performed separately for the H and C pockets, with boxes for the grid-based scoring function (grid spacing of 0.3 ⁇ ) generated from the output of SPHGEN for each pocket.
  • Embodiments of the present inventions were typically prepared using conventional amide bond-coupling conditions between the acid and amine components.
  • PyBOP ((benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate) was established as the most effective reagent for amide couplings.
  • the precursor acid and amines were synthesized using standard methods.
  • N. meningitidis protocol Fresh overnight bacterial plates of N. meningitidis H44/76 (grown on BHI (Brain Heart Infusion) agar plates at 37 ° C and 5%C0 2 ) were resuspended in BHI broth and diluted to a concentration of l .Oxl O 6 bacteria/ml whereupon 200 ⁇ of said dilution was spread evenly onto a fresh BHI plate and allowed to soak in for 20 mins. Meanwhile, the filter discs were impregnated with 10 ⁇ of 256 ⁇ g/mL of the compound to be tested (for example, ADEPIA or ADEPIB) diluted in BHI broth. The impregnated discs were then aseptically laid on the surface and the plates were incubated at 37 ° C and 5%C0 2 overnight. Zones of clearing on plates were measured with an analytical ruler and recorded as the diameter of clearance.
  • E.Coli protocol Fresh overnight bacterial plates of E.Coli (grown on either LB or BHI) agar plates at 37 ° C) were resuspended in BHI broth and diluted to a concentration of l .OxlO 6 bacteria/ml whereupon 200 ⁇ of said dilution was spread evenly onto fresh BHI or LB plates and allowed to soak in for 20 mins. Meanwhile, the filter discs were impregnated with 10 ⁇ of 256 ⁇ g mL of the compound to be tested (for example, ADEPIA or ADEPIB) diluted in BHI broth. The impregnated discs were then aseptically laid on the surface and the plates were incubated at 37 ° C overnight. Zones of clearing on plates were measured with an analytical ruler and recorded as the diameter of clearance.
  • the compound to be tested for example, ADEPIA or ADEPIB

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Abstract

L'invention concerne des activateurs des protéases cylindriques (ACP), en particulier ClpP, et leur rôle pour diagnostiquer et traiter les infections bactériennes. On a identifié un certain nombre d'ACP qui activent une protéase caséinolytique P (ClpP) et peuvent dégrader indépendamment uniquement de petits peptides. En présence d'ACP, on peut activer ClpP pour lui permettre de dégrader de plus grosses protéines, et de supprimer ainsi la spécificité provenant des chaperonnes dépendantes d'ATP. On a découvert que des éléments des ACP présentaient une activité bactéricide. Les ACP représentent des nouvelles classes de composés qui peuvent activer ClpP et être développés en tant que nouveaux antibiotiques potentiels.
PCT/CA2011/001406 2010-12-16 2011-12-16 Activateurs des protéases cylindriques Ceased WO2012079164A1 (fr)

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US9975852B2 (en) 2013-03-04 2018-05-22 Health Sciences North Research Institute Quinoline sulfonyl derivatives and uses thereof
CN109503480A (zh) * 2018-12-14 2019-03-22 中国人民解放军军事科学院军事医学研究院 含喹啉母核的非季铵盐肟类化合物及其医药用途
WO2019243971A1 (fr) * 2018-06-17 2019-12-26 Foundation For Neglected Disease Research Nouveaux composés et leurs procédés d'utilisation
WO2020176654A1 (fr) 2019-02-27 2020-09-03 Madera Therapeutics, LLC Utilisation de la fonction de la protéase caséinolytique p en tant que biomarqueur de réponse médicamenteuse à des agents de type imipridone

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9975852B2 (en) 2013-03-04 2018-05-22 Health Sciences North Research Institute Quinoline sulfonyl derivatives and uses thereof
CN103304635A (zh) * 2013-06-05 2013-09-18 西安交通大学 一种环肽类化合物抗肿瘤的应用及其制备方法
WO2019243971A1 (fr) * 2018-06-17 2019-12-26 Foundation For Neglected Disease Research Nouveaux composés et leurs procédés d'utilisation
CN109503480A (zh) * 2018-12-14 2019-03-22 中国人民解放军军事科学院军事医学研究院 含喹啉母核的非季铵盐肟类化合物及其医药用途
CN109503480B (zh) * 2018-12-14 2021-07-27 中国人民解放军军事科学院军事医学研究院 含喹啉母核的非季铵盐肟类化合物及其医药用途
WO2020176654A1 (fr) 2019-02-27 2020-09-03 Madera Therapeutics, LLC Utilisation de la fonction de la protéase caséinolytique p en tant que biomarqueur de réponse médicamenteuse à des agents de type imipridone
CN113795251A (zh) * 2019-02-27 2021-12-14 马德拉治疗公司 酪蛋白水解蛋白酶p功能作为药物对imipridone样试剂响应的生物标志物的用途
EP3930714A4 (fr) * 2019-02-27 2022-10-26 Madera Therapeutics, LLC Utilisation de la fonction de la protéase caséinolytique p en tant que biomarqueur de réponse médicamenteuse à des agents de type imipridone
US12459945B2 (en) 2019-02-27 2025-11-04 Madera Therapeutics, LLC Use of caseinolytic protease P function as a biomarker of drug response to imipridone-like agents

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