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WO2025045173A1 - Composés antimicrobiens et leurs procédés d'utilisation - Google Patents

Composés antimicrobiens et leurs procédés d'utilisation Download PDF

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WO2025045173A1
WO2025045173A1 PCT/CN2024/115693 CN2024115693W WO2025045173A1 WO 2025045173 A1 WO2025045173 A1 WO 2025045173A1 CN 2024115693 W CN2024115693 W CN 2024115693W WO 2025045173 A1 WO2025045173 A1 WO 2025045173A1
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alkyl
hydrogen
group
cycloalkyl
compound
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Xiao Yang
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Chinese University of Hong Kong CUHK
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Chinese University of Hong Kong CUHK
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    • 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
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present disclosure relates to compounds useful as antimicrobial agents, pharmaceutical compositions comprising the same, and methods of use thereof.
  • RNA polymerase RNA polymerase
  • AMR antimicrobial resistance
  • Bacterial transcription is regulated by numbers of small proteins namely transcription factors. They bind to RNAP to form diverse transcription complexes for regulating RNA synthesis. Therefore, targeting the protein-protein interactions (PPI) in bacterial transcription may inhibit this essential biological process in bacteria and provide a solution for novel antibiotic discovery.
  • PPI protein-protein interactions
  • PPI used to be undruggable due to challenges to designing small molecules that target the large and flat interacting surface of proteins.
  • some critical binding sites on the PPI interacting surface are sufficiently small and appropriate for drug design.
  • Some PPI inhibitors have also been discovered as antimicrobials.
  • n is a whole number selected from 1-3;
  • n is a whole number selected from 1-3;
  • p is a whole number selected from 1-4;
  • X is -S-, -O-, -C (R) 2 -, or -N (R) -;
  • R for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, ether, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; or two instances of R together with the atom they are covalently bonded form a 3-6 membered cycloalkyl or heterocyloalkyl;
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CR 6 2 ) q Y, wherein q is a whole number selected from 0-6; R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or two instances of R 6 together with the carbon they are covalently bonded form a 3-6 membered cycloalkyl; and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O)
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , and -N (R) S (O) 2 R;
  • R 3 is hydrogen or alkyl
  • R 4 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , and -N (R) S (O) 2 R; and
  • R 5 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , and -N (R) S (O) 2 R,
  • X is -S-or -O-.
  • R 5 for each instance is independently selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, perhaloalkoxyl, and halide.
  • R 4 for each instance is independently selected from the group consisting of hydrogen, perhaloalkyl, nitrile, nitro, -C (O) R, -C (O) OR, -C (O) N (R) 2 , -S (O) 2 R, and -S (O) 2 N (R) 2 .
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , and -C (O) N (R) 2 .
  • the compound has Formula 2:
  • n is a whole number selected from 1-3;
  • n is a whole number selected from 1-2;
  • p is a whole number selected from 1-2;
  • X is -S-or -O-
  • R for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, ether, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; or two instances of R together with the atom they are covalently bonded form a 3-6 membered cycloalkyl or heterocyloalkyl;
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CR 6 2 ) q Y, wherein q is a whole number selected from 0-6; R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or two instances of R 6 together with the carbon they are covalently bonded form a 3-6 membered cycloalkyl; and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O)
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , and -C (O) N (R) 2 ;
  • R 3 is hydrogen or alkyl
  • R 4 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , and -N (R) S (O) 2 R; R 5
  • R 7 is perhaloalkyl, nitrile, nitro, -C (O) R, -C (O) OR, -C (O) N (R) 2 , -S (O) 2 R, or -S (O) 2 N (R) 2 ;
  • R 8 for each instance is independently selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, perhaloalkoxyl, and halide.
  • R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CH 2 ) q Y, wherein q is a whole number selected from 0-6; and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -N (R)
  • the compound has Formula 3:
  • n is a whole number selected from 1-3;
  • X is -S-or -O-
  • R for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, ether, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; or two instances of R together with the atom they are covalently bonded form a 3-6 membered cycloalkyl or heterocyloalkyl;
  • R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CH 2 ) q Y, wherein q is a whole number selected from 0-6, and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -S (O) 2
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , and -C (O) N (R) 2 ;
  • R 3 is hydrogen or C 1 -C 3 alkyl
  • R 4 is hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) S (O) 2 R; and
  • R 5 is hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) S (O) 2 R.
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, -OR, and -SR.
  • m is 1 or 2; and R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, halide, and -O- (C 1 -C 6 alkyl) .
  • R 1 is aralkyl or - (CH 2 ) q Y, wherein q is a whole number selected from 0-5, and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -C (O) R, -C (O) OR, -N (R) C (O) R, -N (R) C (O) OR, -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) 2 .
  • the compound has Formula 4:
  • n is a whole number selected from 1-2;
  • R for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, ether, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; or two instances of R together with the atom they are covalently bonded form a 3-6 membered cycloalkyl or heterocyloalkyl;
  • R 1 is aralkyl or - (CH 2 ) q Y, wherein q is a whole number selected from 0-5, and Y is alkynyl, -OR, -CN, cycloalkyl optionally substituted with carbonyl, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, -C (O) OR, N-phthalimide, arginine, -CN, -OR, -C (O) R, -N (R) C (O) OR, -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) 2 ;
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, halide, or -O- (C 1 -C 6 alkyl) ;
  • R 3 is hydrogen or C 1 -C 3 alkyl
  • R 4 is hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) -N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) S (O) 2 R; and
  • R 5 is hydrogen, alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR, -OC (O) N (R) -, -OC (O) OR, -N (R) C (O) N (R) 2 , -S (O) 2 R, -S (O) 2 N (R) 2 , or -N (R) S (O) 2 R.
  • each of R 3 , R 4 and R 5 is hydrogen.
  • R 1 is selected from the group consisting of:
  • R 2 for each instance is independently selected from the group consisting of hydrogen, methyl, fluoride, bromide, chloride, -CF 3 , or -OCH 3 .
  • R 1 is selected from the group consisting of:
  • R 2 for each instance is independently selected from the group consisting of hydrogen, methyl, fluoride, bromide, chloride, -CF 3 , or -OCH 3 ; and R 3 is hydrogen.
  • the compound has Formula 5:
  • R 1 is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound described herein and at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipient.
  • a third aspect provided herein is a method of treating a bacterial infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the subject.
  • the bacterial infection results from a Graham positive bacteria.
  • the bacterial infection results from a Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Methicillin-resistant Staphylococcus aureus, or vancomycin-resistant Staphylococcus aureus infection.
  • the bacterial infection results from an antibiotic resistant Staphylococcus aureus infection or from an antibiotic resistant Streptococcus pneumoniae infection.
  • Figure 1 depicts the structure of A) the E. coli RNAP holoenzyme crystal complex and B) interactions at the interface of ⁇ 2.2 and ⁇ ’CH.
  • Figure 2 depicts A) structures of C3 and C3-005; B) docking model of C3 to ⁇ ’CH (surface view) .
  • Figure 3 depicts antimicrobial activity (MIC ⁇ g/mL) of the selected compounds against clinically important Gram-positive pathogens.
  • EFAE Enterococcus faecalis ATCC 19433
  • SAUR a Staphylococcus aureus ATCC 25923,
  • SAUR b S. aureus ATCC 29213,
  • SEPI Staphylococcus epidermidis ATCC 12228
  • SSAP Staphylococcus saprophyticus ATCC 15305
  • SPNE a Streptococcus pneumoniae ATCC 49619
  • SPNE b S.pneumoniae strain TCH8431 (HM-145)
  • SPNE c S.
  • Figure 4 depicts antimicrobial activity (MIC ⁇ g/mL) of the selected compounds against methicillin-resistant Staphylococcus aureus (MRSA) strains.
  • HA-MRSA 232ST5: W-232 ST5, 233ST5: W-233 ST5, 234ST5: W-234 ST5, 235ST5: W-235 ST5, BAA-43: S. aureus ATCC BAA-43, BAA-44: S. aureus ATCC BAA-44, ST239: HA-MRSA 07B082243 ST239.
  • CA-MRSA 45ST59: W-45 ST59, 46ST59: W-46 ST59, 47ST59: W-47 ST30, 48ST217: W-48 ST217, ST22: CA-MRSA 11B086169 ST22, USA300: CA-MRSA strain USA300.
  • Cip Ciprofloxacin
  • Gen Gentamicin
  • Oxa Oxacillin
  • Van Vancomycin.
  • M20-01 CUHK_M20_01
  • M20-02 CUHK_M20_02
  • M20-03 CUHK_M20_03
  • M20-04 CUHK_M20_04
  • M20-05 CUHK_M20_05.
  • Figure 5 depicts antimicrobial activity (MIC ⁇ g/mL) of the selected compounds against VRSA strains.
  • VRSA NR-46410: S. aureus strain HIP11714, NR-46411: S. aureus strain HIP11983, NR-46412: S. aureus strain HIP13170, NR-46413: S. aureus strain HIP13419, NR-46414: S. aureus strain HIP14300, NR-46415: S. aureus strain HIP15178, NR-46416: S. aureus strain AIS2006032, NR-46417: S. aureus strain AIS2006045, NR-46418: S. aureus strain 71080, NR-46419: S.
  • Cip Ciprofloxacin
  • Gen Gentamicin
  • Oxa Oxacillin
  • Van Vancomycin.
  • Figure 6 depicts A) epifluorescence microscopic image of B. subtilis BS1048; B) B. subtilis BS1048 treated with rifampicin; C) B. subtilis BS1048 treated with chloramphenicol; D) B. subtilis BS1048 treated with 5d (from left to right: 1, 2, 4, and 8 ⁇ g/mL) .
  • Figure 7 depicts compounds docked to ⁇ ′CH using AutoDock Vina.
  • A binding poses of 5d and 7d in complex with ⁇ ′CH. Details of the interactions between ⁇ ′CH and 5d (B) and 7d (C) .
  • the images were generated by PyMol.
  • Patent law e.g., they can mean “includes” , “included” , “including” , and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the present invention.
  • treatment refers to reducing or ameliorating a disorder/disease and/or symptoms associated therewith. It will be appreciated, although not precluded, treating a disorder or condition does not require that the disorder, condition, or symptoms associated therewith be completely eliminated. In certain embodiments, treatment includes prevention of a disorder or condition, and/or symptoms associated therewith.
  • prevention or “prevent” as used herein refers to any action that inhibits or at least delays the development of a disorder, condition, or symptoms associated therewith.
  • Prevention can include primary, secondary and tertiary prevention levels, wherein: a) primary prevention avoids the development of a disease; b) secondary prevention activities are aimed at early disease treatment, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms; and c) tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.
  • terapéuticaally effective amount means that amount of the compound or pharmaceutical agent that elicits a biological and/or medicinal response in a cell culture, tissue system, subject, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • alkyl groups include methyl-, ethyl-, propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl) , pentyl groups (e.g., 1-methylbutyl, 2-methylbutyl, iso-pentyl, tert-pentyl, 1, 2-dimethylpropyl, neopentyl, and 1-ethylpropyl) , hexyl groups, and the like.
  • an alkyl group can have 1 to 40 carbon atoms (i.e., C1-40 alkyl group) , for example, 1-30 carbon atoms (i.e., C1-30 alkyl group) .
  • an alkyl group can have 1 to 6 carbon atoms, and can be referred to as a "lower alkyl group. " Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl) , and butyl groups (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl) .
  • alkyl groups can be optionally substituted as described herein.
  • An alkyl group is generally not substituted with another alkyl group, an alkenyl group, or an alkynyl group.
  • alkenyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds.
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like.
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene) .
  • an alkenyl group can have 2 to 40 carbon atoms (i.e., C2-40 alkenyl group) , for example, 2 to 20 carbon atoms (i.e., C2-20 alkenyl group) .
  • alkenyl groups can be substituted as described herein.
  • An alkenyl group is generally not substituted with another alkenyl group, an alkyl group, or an alkynyl group.
  • cycloalkyl by itself or as part of another substituent means, unless otherwise stated, a monocyclic hydrocarbon having between 3-12 carbon atoms in the ring system and includes hydrogen, straight chain, branched chain, and/or cyclic substituents.
  • exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, silicon, sulfur, phosphorus, and selenium.
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., having a bond in common with) together or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or heterocycloalkyl rings.
  • An aryl group can have 6 to 24 carbon atoms in its ring system (e.g., C6-24 aryl group) , which can include multiple fused rings.
  • a polycyclic aryl group can have 8 to 24 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure.
  • aryl groups having only aromatic carbocyclic ring include phenyl, 1-naphthyl (bicyclic) , 2-naphthyl (bicyclic) , anthracenyl (tricyclic) , phenanthrenyl (tricyclic) , pentacenyl (pentacyclic) , and like groups.
  • polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5, 6-bicyclic cycloalkyl/aromatic ring system) , cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6, 6-bicyclic cycloalkyl/aromatic ring system) , imidazoline (i.e., a benzimidazolinyl group, which is a 5, 6-bicyclic cycloheteroalkyl/aromatic ring system) , and pyran (i.e., a chromenyl group, which is a 6, 6-bicyclic cycloheteroalkyl/aromatic ring system) .
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • heteroaryl refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from oxygen (O) , nitrogen (N) , sulfur (S) , silicon (Si) , and selenium (Se) or a polycyclic ring system where at least one of the rings present in the ring system is aromatic and contains at least one ring heteroatom.
  • Polycyclic heteroaryl groups include those having two or more heteroaryl rings fused together, as well as those having at least one monocyclic heteroaryl ring fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings.
  • a heteroaryl group as a whole, can have, for example, 5 to 24 ring atoms and contain 1-5 ring heteroatoms (i.e., 5-20 membered heteroaryl group) .
  • the heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain O-O, S-S, or S-O bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide thiophene S-oxide, thiophene S, S-dioxide) .
  • heteroaryl groups include, for example, the 5-or 6-membered monocyclic and 5-6 bicyclic ring systems shown below: where T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl) , SiH 2 , SiH (alkyl) , Si (alkyl) 2 , SiH(arylalkyl) , Si (arylalkyl) 2 , or Si (alkyl) (arylalkyl) .
  • T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl) , SiH 2 , SiH (alkyl) , Si (alkyl) 2 , SiH(arylalkyl) , Si (arylalkyl) 2 , or Si (alkyl) (arylalkyl) .
  • heteroaryl rings examples include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, lH-indazolyl, 2H-indazo
  • heteroaryl groups include 4, 5, 6, 7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like.
  • heteroaryl groups can be substituted as described herein.
  • heteroaryl groups can be optionally substituted.
  • optionally substituted refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a substituent as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like
  • nitro is art-recognized and refers to -NO 2 ;
  • halogen is art-recognized and refers to -F, -Cl, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl and “sulfone” is art-recognized and refers to -SO 2 -.
  • Halide designates the corresponding anion of the halogens.
  • the symbol or or or in a chemical structure represents a position from where the specified chemical structure is bonded to another chemical structure.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • n is a whole number selected from 1-3;
  • n is a whole number selected from 1-3;
  • p is a whole number selected from 1-4;
  • A is a moiety having the structure:
  • X is -S-, -O-, -C (R) 2 -, or -N (R) -;
  • R for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, ether, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; or two instances of R together with the atom they are covalently bonded form a 3-6 membered cycloalkyl or heterocyloalkyl;
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CR 6 2 ) q Y, wherein q is a whole number selected from 0-6; R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or two instances of R 6 together with the carbon they are covalently bonded form a 3-6 membered cycloalkyl; and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O)
  • R 1 can be C 2 -C 12 alkyl, C 3 -C 12 alkyl, C 4 -C 12 alkyl, C 3 -C 10 alkyl, C 3 -C 8 alkyl, C 3 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or - (CR 2 ) q Y, wherein R 6 for each instance is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyl, q is a whole number selected from 0-6, and Y is alkynyl, cycloalkyl optionally substituted with a carbonyl moiety, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, N-phthalimide, arginine, -CN, -OR, -SR, -N (R) 2 , -C (O) R, -
  • R 1 is cycloalkyl, aralkyl, or - (CR 2 ) q Y, wherein q is a whole number selected from 1-4, and Y is cycloalkyl, heteroaryl, heterocycloalkyl, 3, 3-difluoropyrrolidin-1-yl, or -N (R) 2 .
  • R 1 moieties include but are not limited to:
  • R 2 for each instance can be independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , and -C (O) N (R) 2 .
  • R 2 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, -OR, and -SR.
  • At least one R 2 is C 1 -C 6 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 1 -C 3 perhaloalkyl, C 1 -C 2 perhaloalkyl, halide, -O- (C 1 -C 6 alkyl) , -O- (C 1 -C 3 alkyl) , or -O- (C 1 -C 2 alkyl) .
  • at least one R 2 is methyl, -CF 3 , fluoride, chloride, bromide, or -OMe.
  • R 3 can be hydrogen, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, or C 1 -C 2 alkyl.
  • R 3 is hydrogen, methyl, or ethyl.
  • the ester may be metabolised or hydrolysed under physiological conditions thereby forming the corresponding carboxylic acid, i.e., wherein R 3 is hydrogen.
  • R 4 for each instance can be independently selected from the group consisting of hydrogen, perhaloalkyl, nitrile, nitro, -C (O) R, -C (O) OR, -C (O) N (R) 2 , -S (O) 2 R, and -S (O) 2 N (R) 2 .
  • at least one R 4 is nitrile, nitro, -C (O) OR, -C (O) N (R) 2 , -S (O) 2 R, or -S (O) 2 N (R) 2 .
  • at least one R 4 is nitro.
  • R 5 for each instance can be independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, halide, nitrile, nitro, azido, -OR, -SR, -N (R) 2 , and -C (O) N (R) 2 .
  • at least one or at least two R 5 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 perhaloalkyl, halide, nitrile, or nitro.
  • at least two R 5 are methyl, halomethyl, perhalomethyl, fluoride, chloride, or nitrile.
  • at least two R 5 are methyl, FCH 2 -, F 2 CH-, CF 3 -, chloride, or nitrile.
  • the compound has Formula 5:
  • R 1 is selected from the group consisting of:
  • the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein and at least one pharmaceutically acceptable excipient and/or pharmaceutically acceptable carrier.
  • the compounds described herein and their pharmaceutically acceptable salts can be administered to a subject either alone or in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.
  • the compound can be administered parenterally.
  • Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical.
  • compositions which comprise a therapeutically-effective amount of the compound described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present disclosure may be specially formulated for administration in liquid form, including those adapted for the following: (1) parenteral administration, for example, by intravenous as, for example, a sterile solution or suspension.
  • certain embodiments of the compound described herein may contain a basic functional group, such as amino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present disclosure. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the bromide, chloride, sulfate, bisulfate, carbonate, bicarbonate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • the pharmaceutically acceptable salts of the compounds of the present disclosure include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compound described herein may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of the compound of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, solubilizing agents, buffers and antioxidants can also be present in the compositions.
  • Methods of preparing the pharmaceutical comprising the compound include the step of bringing into association a compound described herein with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid carriers (liquid formulation) , liquid carriers followed by lyophilization (powder formulation for reconstitution with sterile water or the like) , or finely divided solid carriers, or both, and then, if necessary, shaping or packaging the product.
  • compositions of the present disclosure suitable for parenteral administration comprise one or more compounds described herein in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars (such as sucrose) , alcohols, non-ionic surfactants (such as Tween 20) , antioxidants, buffers, bacteriostats, chelating agents, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms upon the compounds of the present disclosure may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • provided herein is a method of treating a bacterial infection in a subject in need thereof, the method comprising the step of administering a therapeutically effective amount of a compound described herein to the subject.
  • Exemplary bacterial infections include, but are not limited to, pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S.
  • haemolyticus or Peptostreptococcus spp.
  • pharyngitis rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum
  • respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae
  • blood and tissue infections including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E.
  • faecium E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracylines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.
  • known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracylines and macrolides
  • uncomplicated skin and soft tissue infections and abscesses uncomplicated skin and soft tissue infections and abscesses
  • puerperal fever related to infection by Staphylococcus aureus coagulase-negative staphylococci
  • Streptococcus pyogenes Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci) , viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S.
  • aureus food poisoning and toxic shock syndrome
  • Groups A, B, and C streptococci ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.
  • MAC Mycobacterium avium complex
  • Bacterial infections and disorders related to such infections include the following: bovine respiratory disease related to infection by P. haemolytica, P.
  • cow enteric disease related to infection by E. coli or protozoa i.e., coccidia, cryptosporidia, etc.
  • coli Lawsonia intracellularis, Salmonella, or Serpulina hyodysinteriae
  • cow footrot related to infection by Fusobacterium spp.
  • cow metritis related to infection by E coli
  • cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus
  • cow pink-eye related to infection by Moraxella bovis
  • cow premature abortion related to infection by protozoa (i.e. neosporium)
  • urinary tract infection in dogs and cats related to infection by E. coli skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, coagulase neg. Staphylococcus or P.
  • the bacteria is selected from the group consisting of Streptococcus agalactiae, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus saprophyticus, and Enterococcus faecium.
  • the bacteria is SAUR ATCC 25923, SAUR ATCC 29213, or SPNE ATCC 49619.
  • the subject can be a canine, feline, bovine, equine, non-human primate, or human. In certain embodiments, the subject is a human.
  • the compounds described herein are bactericidal or bacteriostatic.
  • provided herein is the use of a compound described herein for the preparation of a medicament for the treatment of a bacterial infection.
  • a method of treating a bacterial infection in a subject in need thereof comprising the step of co-administering a therapeutically effective amount of a compound described herein and an antibacterial agent to the subject.
  • the antibacterial agent can be any antibacterial agent known in the art.
  • RNAP housekeeping sigma
  • ⁇ housekeeping sigma
  • the latter is a small protein highly conserved in bacteria (namely ⁇ A in Gram-negative bacteria and ⁇ 70 in Gram-negative bacteria) and binds to RNAP to initiate bacterial transcription by recognizing DNA promoters (Fig. 1A) .
  • the important amino acids at RNAP ⁇ ’ subunit clamp-helix region ( ⁇ ’CH) for binding to ⁇ region 2.2 (Fig. 1B) were validated, followed by adopting structure-based drug design and in silico screening of a drug-like compound library to identify several hit compounds including C3. Meanwhile, other RNAP- ⁇ PPI inhibitors have also been identified.
  • the carbonyl, methylene, and aminomethylene linker provided superior antimicrobial activity to analogs with the amide linker.
  • the sulfonamide moiety is selected as the linker to connect the diphenylsulfide moiety and the benzoic acid moiety to examined the structural requirements for the linker.
  • the benzoic acid moiety is clamped by ⁇ ’CH R278 and R281 (Fig. 1B &2B) , a substituted benzoic acid was designed to probe the small semi-pocket formed by ⁇ ’CH for binding and examine the effect of substitutions on benzoic acid on the antimicrobial activity.
  • a sulfonamide has a more acidic proton suitable for substitution reactions. Modification of the sulfonamide nitrogen using different groups was explored to determine their impact on the antimicrobial activity of new analogs.
  • Alkylamine derivatives were also synthesized as depicted in Scheme 3. Alkylation of 4c with 1, 4-dibromobutane in the presence of K 2 CO 3 yielded compound 8 in 72 %yield, which was further aminated with various secondary amines to provide compounds 9a –9d. The methyl esters were finally hydrolyzed to furnish N-alkylamines 10a –10d.
  • SPNE S. pneumoniae ATCC 49619
  • SAUR a S. aureus ATCC 29213
  • SAUR b S. aureus ATCC 29523
  • SPNE S. pneumoniae ATCC 49619
  • SAUR a S. aureus ATCC 29213
  • SAUR b S. aureus ATCC 29523
  • Fig. 3 demonstrated the extensive antimicrobial potential of the compounds described herein against a wide range of Gram-positive bacteria, including clinically complex pathogens such as S. epidermidis, S. saprophyticus, S. pyogenes, and S. agalactiae, with most MICs ranging between 2 to 8 ⁇ g/mL.
  • 5d, 7a, 7b and 7d presented robust antimicrobial activity against multiple Gram-positive bacteria, with an impressive MIC as low as 1 ⁇ g/mL against S. pneumoniae.
  • 5d exhibited significant potency against Streptococci (MIC 1-2 ⁇ g/mL)
  • 7a demonstrated remarkable efficacy against S. epidermidis (MIC 2 ⁇ g/mL) , showcasing the potential of our compounds in treating bacterial infections.
  • Methicillin-resistant Staphylococcus aureus (MRSA) strains represent some of the most challenging bacterial strains for treatment due to antibiotic resistance, including resistance to the “last resort” antimicrobial therapeutic agent, vancomycin, currently available in the market.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • HA- hospital-acquired
  • CA- community-acquired
  • VRSA vancomycin-resistant Staphylococcus aureus
  • the HA-MRSA strains included W-231 ST45, W-232 ST5, W-233 ST5, W-234 ST-5, W-235 ST5, ATCC BAA-43, ATCC BAA-44, and ST239.
  • the CA-MRSA strains included W-45 ST59, W-46 ST59, W-47 ST30, W-48 ST217, ST22, ST338, and USA300.
  • M20 MRSA strains denoted as M20 were also included (N. Barua, et. al, Comparative Study of Two-Dimensional (2D) vs.
  • MRSA Staphylococcus aureus
  • the laboratory strains of known resistant mechanisms were included, for example, SA-APH2”-AAC6’, SA-APH3’, and SA-ANT4’, which are resistant to aminoglycosides due to the presence of aminoglycoside-modifying enzymes (AMEs) .
  • SA-RN4220-pUL5054 was also included, which exhibits macrolide resistance, as well as SA-1199B, which is known to be resistant to fluoroquinolone.
  • the compounds demonstrated antimicrobial activity against the tested MRSA strains, with the most potent MIC as low as 2 ⁇ g/mL.
  • This efficacy outperformed currently used antibiotics such as ciprofloxacin, gentamicin, and oxacillin, especially for treating specific strains.
  • most of the MRSA strains selected were resistant to oxacillin, the current first-line antibiotic used in the USA for MRSA infections, as well as other common drugs like the protein-synthesis inhibitor gentamicin.
  • the compounds’ antimicrobial activity against MRSA strains with various individual resistance mechanisms indicated diverse modes of action without overlapping with existing antibiotics.
  • 5d, 7b, 7c, 7d, and 7i maintained consistent MIC values, ranging from 2 to 8 ⁇ g/mL, against a broad range of MRSA strains, particularly the aminoglycosides-resistant strain SA-APH3’, highlighting their potential for further development as treatments for MRSA infections.
  • VRSA strains used were provided by the Network on Antimicrobial Resistance in S. aureus (NARSA) for distribution by BEI Resources, NIAID, NIH and administered by ATCC (Manassas, Virginia, United States) , which include: NR-46410 (S. aureus strain HIP11714) , NR-46411 (S. aureus strain HIP11983) , NR-46412 (S. aureus strain HIP13170) , NR-46413 (S. aureus strain HIP13419) , NR-46414 (S. aureus strain HIP14300) , NR-46415 (S. aureus strain HIP15178) , NR-46416 (S.
  • NARSA Network on Antimicrobial Resistance in S. aureus
  • aureus strain AIS 2006032) NR-46417 (S. aureus strain AIS 2006045) , NR-46418 (S. aureus strain 71080) , NR-46419 (S. aureus strain AIS 080003) , NR-46420 (S. aureus strain AIS 1000505) , NR-46421 (S. aureus strain AIS 1001095) , and NR-46422 (S. aureus strain AID 1001123) .
  • the series of C3 compounds exhibited significant antibacterial effects against a range of pathogenic bacteria, including notoriously difficult-to-treat strains such as MRSA and VRSA.
  • the unsubstituted sulfonamidyl compounds (5a-5j) maintained strong antimicrobial activity against S. pneumoniae than other Gram-positive bacteria, while the substitutions at the sulfonamidyl nitrogen improved the general antimicrobial activity of the resulting compounds (7a-7k) against S. aureus, which were demonstrated by the testing results against MRSA and VRSA strains.
  • 5d and 7d stood out with the highest antibacterial activity against a variety of bacterial strains that are resistant to currently available antibiotics.
  • RNAP-targeting chloramphenicol did not affect RNAP function, while RNAP-targeting rifampicin could delocalize the transcription foci (Fig. 6B) and ribosome-targeting chloramphenicol did not affect it (Fig. 6C) .
  • the molecular docking was performed as displayed in Fig. 7 for the calculated binding poses of 5d and 7d in complex with ⁇ ′CH.
  • the benzoic acid moieties of both ligands located in the positive charged area formed by residues include Arg275 and Arg278, while the 3, 4-dichlorophenyl ring fitted in a small pocket formed by hydrophobic residues.
  • the carboxyl group of 5d formed two hydrogen bonds with Arg278 (O...H ) and Asn274 (O...H ) of ⁇ ′CH.
  • a H-bond was formed between the nitro group and Arg275 (O...H ) (Fig. 7B) .
  • Fig. 7C showed the interactions between 7d and ⁇ ′CH.
  • RNAP- ⁇ PPI inhibitors were developed as RNAP- ⁇ PPI inhibitors.
  • C3-005 sulfonamidyl derivatives of C3-005 (sigmacidins)
  • the sulfonamidyl derivatives of C3-005 have potential for further development.
  • the sulfonamidyl nitrogen provided an additional and appropriate position for substitution without diminishing antimicrobial activity
  • the substituted derivatives demonstrated improved antimicrobial activity against S. aureus, including MRSA and VRSA.
  • More structurally diverse derivatives of sigmacidin with excellent antimicrobial activity are expected to enrich the molecular pool of RNAP- ⁇ PPI inhibitors for biomedical research and drug development..
  • the methyl esters of compounds (4a –4n) (0.1 mmol) were hydrolyzed with 1 M NaOH in dioxane (1 : 1) at 50 °C overnight. The mixture was then diluted with a small amount of water and washed twice by DCM. The aqueous solution was acidified by the addition of 2 M HCl. The precipitates were collected by filtration and washed with water to provide the title compounds 5a –5n.
  • the methyl esters of the title compounds (6a –6k) (0.1 mmol) were hydrolyzed with 1 M NaOH in dioxane (1:1) at 50 °C overnight. The mixture was then diluted with a small amount of water and washed twice with DCM. The aqueous solution was acidified by the addition of 2 M HCl. The precipitate was collected by filtration and washed with water to provide the title compounds (7a –7k) .
  • the methyl esters of the title compounds (9a –9d) (0.1 mmol) were hydrolyzed with 1 M NaOH in dioxane (1 : 1) at 50 °C overnight. The mixture was then diluted with a small amount of water and washed twice with DCM. The aqueous solution was acidified by the addition of 2 M HCl. The precipitate was collected by filtration and washed with water to provide the title compounds 10a –10d.
  • the antimicrobial activity of the compounds was determined by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (Clinical &Laboratory Standards Institute, 2020) .
  • the test medium was cation-adjusted Mueller-Hinton broth (MHB) if not specified elsewhere or brain heart infusion (BHI) broth as indicated in the main text.
  • Serial two-fold dilutions of the tested compound were performed for the tested chemicals starting from 256 ⁇ g/mL to 0.25 ⁇ g/mL, and the bacterial cell inoculum was adjusted to approximately 5 ⁇ 10 5 CFU per mL.Results were taken after 20-hour of incubation at 37°C.
  • the MIC was defined as the lowest concentration of antibiotic with no visible growth. Experiments were performed in duplicates.
  • the bacterial panel we used consisted of 3 Gram-positive pathogens on most recent “WHO priority pathogens list for guiding R&D of new antibiotics” consisting of Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumonia, Klebsiella pneumoniae, Actinobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli.
  • the compounds demonstrated broad-spectrum antimicrobial activity against all tested Gram-positive bacteria as shown in Table 5.
  • B. subtilis strain BS1048 was grown on LB agar plate mixed with 5 mg/mL chloramphenicol and 0.5% (w/v) xylose. A single colony was incubated in LB medium mixed with 5 mg/mL chloramphenicol and 0.5% (w/v) xylose at 37 °C until OD 600 ⁇ 0.6. Chloramphenicol, rifampicin, or compound was then added to the culture and allowed to incubate for further 15 min. 2.5 ⁇ L of cell culture was placed onto 1.2%freshly made agarose plate and covered with a coverslip prior to imaging.
  • Nikon eclipse Ti2-E live-cell fluorescence imaging system equipped with 63 ⁇ /1.4 oil objective and LED illumination system was used to capture the fluorescence images. The fluorescence images were processed with Nikon NIS-Elements and MetaMorph software.

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Abstract

L'invention concerne des composés utiles dans le traitement d'infections bactériennes, des produits pharmaceutiques les comprenant, et des procédés d'utilisation et de préparation de ceux-ci. Les composés sont supposés cibler des interactions protéine-protéine impliquant une ARN polymérase et des facteurs sigma. Les composés présentent une activité antimicrobienne à des concentrations inhibitrices minimales (CMI) de 1 pg/mL, démontrant une efficacité contre les bactéries. En outre, ces composés ont démontré une faible cytotoxicité.
PCT/CN2024/115693 2023-08-30 2024-08-30 Composés antimicrobiens et leurs procédés d'utilisation Pending WO2025045173A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030191146A1 (en) * 1999-11-10 2003-10-09 The Trustees Of Columbia University In The City Of New York Novel antimicrobial activity of gemfibrozil and related compounds and derivatives and metabolites thereof
WO2004018461A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Derives d'acide benzoique antibacteriens
WO2004018414A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Agents antibacteriens
WO2008114831A1 (fr) * 2007-03-20 2008-09-25 National University Corporation Okayama University Agent antibactérien comprenant un groupe sulfamide
WO2015085238A1 (fr) * 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibiteurs de lpxc
CN112638909A (zh) * 2018-06-27 2021-04-09 香港理工大学 具有抗菌活性的化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030191146A1 (en) * 1999-11-10 2003-10-09 The Trustees Of Columbia University In The City Of New York Novel antimicrobial activity of gemfibrozil and related compounds and derivatives and metabolites thereof
WO2004018461A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Derives d'acide benzoique antibacteriens
WO2004018414A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Agents antibacteriens
WO2008114831A1 (fr) * 2007-03-20 2008-09-25 National University Corporation Okayama University Agent antibactérien comprenant un groupe sulfamide
WO2015085238A1 (fr) * 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibiteurs de lpxc
CN112638909A (zh) * 2018-06-27 2021-04-09 香港理工大学 具有抗菌活性的化合物

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