Inhibitors of ftsz and uses thereof

Abstract

The invention relates to inhibitors of FtsZ polymerization and uses thereof.

1 - 42 . (canceled) 
     
     
         43 . A method of inhibiting bacterial growth comprising contacting a bacterium with an effective amount of one or more compounds having the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2  are CH or N, and at least one of X 1  and X 2  are N; 
 b) S 1  is an organic radical comprising 1 to 8 carbon atoms; 
 c) S 2 , S 3 , and S 4  are independently selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms; 
 d) or a salt thereof. 
 
     
     
         44 . The method of  claim 43 , wherein the bacterium is antibiotic resistant. 
     
     
         45 . The method of  claim 43 , wherein the bacterium is gram positive. 
     
     
         46 . The method of  claim 45 , wherein the gram positive bacterium is selected from the group consisting of:  M. tuberculosis, M. bovis, M. typhimurium, M. bovis  strain BCG, BCG substrains,  M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium  subspecies  paratuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus equi, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Listeria ivanovii, Bacillus anthracis, B. subtilis, Nocardia asteroides , and other  Nocardia  species,  Streptococcus viridans  group,  Peptococcus  species,  Peptostreptococcus  species,  Actinomyces  israelii and other  Actinomyces  species, and  Propionibacterium acnes.    
     
     
         47 . The method of  claim 43 , wherein the bacterium is gram negative. 
     
     
         48 . The method of  claim 47 , wherein the gram negative bacterium is selected from the group consisting of:  Clostridium tetani, Clostridium perfringens, Clostridium botulinum , other  Clostridium  species,  Pseudomonas aeruginosa , other  Pseudomonas  species,  Campylobacter  species,  Vibrio cholerae, Ehrlichia  species,  Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida , other  Pasteurella  species,  Legionella pneumophila , other  Legionella  species,  Salmonella typhi , other  Salmonella  species,  Shigella  species  Brucella abortus , other  Brucella  species,  Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi , other  Hemophilus  species,  Yersinia pestis, Yersinia enterolitica , other  Yersinia  species,  Escherichia coli, E. hirae  and other  Escherichia  species, as well as other Enterobacteria,  Brucella abortus  and other  Brucella  species,  Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fudobascterium nucleatum, Provetella  species, and  Cowdria ruminantium.    
     
     
         49 . The method of  claim 47 , wherein the compound is used in conjunction with a permeability enhancer, wherein the permeability enhancer allows the compound to cross the cell envelope of the bacterium. 
     
     
         50 . The method of  claim 49 , wherein the permeability enhancer is selected from the group consisting of polymyxin B, surface active agents, defensins, other membrane active peptides and chelating agents. 
     
     
         51 . The method of  claim 43 , further comprising contacting the bacterium with a permeability enhancer. 
     
     
         52 . The method of  claim 51 , wherein the permeability enhancer is selected from the group consisting of polymyxin B, surface active agents, defensins, other membrane active peptides and chelating agents. 
     
     
         53 . The method of  claim 43 , wherein the compound has a molecular weight of less than about 500 grams per mole. 
     
     
         54 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) S 1  is an alkyl group comprising 1 to 4 carbon atoms; 
 b) S 2  is a halogen, amino, hydroxy, or an organic radical comprising 1 to 26 carbon atoms selected from alkyl, alkoxy, monosubstituted amino, or disubstituted amino; 
 c) S 2  and S 3  
 (i) are independent substituents that can be independently selected from a halogen, amino, hydroxy, or an organic radical comprising 1-26 carbon atoms, or 
 (ii) together form a heteroaryl or heterocyclic radical comprising 5, 6, or 7 ring atoms, optionally substituted with 1, 2, or three ring substituents selected from halogen, amino, or organic radicals comprising 1 to 12 carbon atoms. 
 
 
     
     
         55 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2 , are CH or N, and at least one of X 1  and X 2  are N; 
 b) X 3  is CH, N, NH, O, or S, 
 C) X 4  is a halogen, oxygen, sulfur, or phosphorus atom, amino, NH, or an organic radical comprising 1-26 carbon atoms, 
 d) R 1  is an alkyl radical comprising 1 to 4 carbon atoms, 
 e) R 2  is an optional radical selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms, 
 f) R 3  and an optional R 3 ′ radical that may be present or absent are independently selected from hydrogen, halogen, or an organic radical comprising 1 to 26 carbon atoms, 
 g) Cn comprises one or two optional ring carbon atoms, wherein each optional ring carbon atom has one or two substituent radicals independently selected from hydrogen, halogen, hydroxy, amino, or an organic radical comprising 1 to 26 carbon atoms, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) R 1  is an alkyl group comprising 1 to 4 carbon atoms, 
 b) R 2 —X 4  is an amino or a mono-substituted amino radical comprising 1 to 26 carbon atoms, 
 c) R 3  and R 4  are independently selected from hydrogen, halogen, or an organic radical comprising 1 to 12 carbon atoms, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         57 . The method of  claim 56 , wherein R 3  and R 4  are independently selected from hydrogen, alkyl or alkoxy radicals comprising 1 to 18 carbon atoms, aryl radicals comprising 6 to 18 carbons, or heteroaryl radicals comprising 1 to 18 ring carbons. 
     
     
         58 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2 , are CH or N, and at least one of X 1  and X 2  are N; 
 b) X 3  is CH, N, NH, O, or S, 
 c) X 4  is a halogen, oxygen, sulfur, or phosphorus atom, amino, NH, or an organic radical comprising 1-26 carbon atoms, 
 d) R 1  is an alkyl radical comprising 1 to 4 carbon atoms; 
 e) R 2  is selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms. 
 f) R 3 , R 4 , R 3 ′, R 4 ′, radicals are independently selected from hydrogen, halogen, or an organic radical comprising 1 to 26 carbon atoms 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2 , are CH or N, and at least one of X 1  and X 2  are N; 
 b) X 3  is CH, N, NH, O, or S, 
 c) X 4  is a halogen, oxygen, sulfur, or phosphorus atom, amino, NH, or an organic radical comprising 1-26 carbon atoms, 
 d) R 1  is an alkyl radical comprising 1 to 4 carbon atoms; 
 e) R 2  is an optional radical selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms. 
 f) R 3 , R 4 , R 5 , and the optional R 3 ′, R 4 ′, and R 5 ′ radicals are independently selected from hydrogen, halogen, or an organic radical comprising 1 to 26 carbon atoms, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) R 1  is an alkyl radical comprising 1 to 4 carbon atoms; 
 b) the R 3 , R 4 , R 5 , R 4′ , and R 5′  radicals are independently selected from hydrogen, halogen, or an organic radical comprising 1 to 26 carbon atoms, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         61 . The method of  claim 43 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         a) X 1  and X 2 , are CH or N, and at least one of X 1  and X 2  are N; 
         b) X 3  is CH, N, NH, O, or S, 
         c) X 4  is a halogen, oxygen, sulfur, or phosphorus atom, amino, NH, or an organic radical comprising 1-26 carbon atoms, 
         d) R 1  is an alkyl radical comprising 1 to 4 carbon atoms; 
         e) R 2  is an optional radical selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms. 
         f) Cn is hydrogen, or an organic radical comprising 1 to 26 carbon atoms, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         62 . The method of  claim 43 , wherein the compound has the formula:
 a) [5,6-Diamino-4-(2-hydroxy-1-methyl-3-phenoxypropylamino)-pyridin-2-yl]-carbamic acid ethyl ester;   b) [8-(4-Diethylamino-1-methyl-butylamino)-2,3-diphenyl-pyrido[2,3-b]pyrazin-6-yl]-carbamic acid ethyl ester;   c) (1-Amino-8-phenyl-6,7-dihydro-5H-2,5,9-triazabenzocyclohepten-3-yl)-carbamic acid ethyl ester;   d) [2,3-Diphenyl-8-(4-sulfamoyl-benzylamino)-pyrido[2,3-b]pyrazin-6-yl]-carbamic acid ethyl ester;   e) (5-Amino-3-butyl-2-methyl-1,2-dihydro-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid ethyl ester;   f) (5-Amino-2,3-diphenyl-2H-pyrido[4,3-b][1,4]oxazin-7-yl)-carbamic acid ethyl ester;   g) (5-Ethoxy-2,3-diphenyl-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid ethyl ester;   h) (5-Amino-2,3-diphenyl-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid ethyl ester;   i) (5-Amino-3-{[(4-methoxy-phenyl)-methyl-amino]-methyl}-1,2-dihydro-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid ethyl ester; or   j) [5-Amino-3-(4-butylcarbamoyloxy-phenyl)-2-methyl-1,2-dihydro-pyrido[3,4-b]pyrazin-7-yl]-carbamic acid ethyl ester;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         63 . A method of killing a bacterium comprising contacting the bacterium with an effective amount of one or more compounds having the structure 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2  are CH or N, and at least one of X 1  and X 2  are N; 
 b) S 1  is an organic radical comprising 1 to 8 carbon atoms; 
 c) S 2 , S 3 , and S 4  are independently selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms; 
 d) or a salt thereof. 
 
     
     
         64 . The method of  claim 63 , wherein the bacterial infection is a gram positive bacterial infection. 
     
     
         65 . The method of  claim 64 , wherein the bacterial infection is selected from the group consisting of:  M. tuberculosis, M. bovis, M. typhimurium, M. bovis  strain BCG, BCG substrains,  M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium  subspecies  paratuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus equi, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Listeria ivanovii, Bacillus anthracis, B. subtilis, Nocardia asteroides , and other  Nocardia  species,  Streptococcus  viridans group,  Peptococcus  species,  Peptostreptococcus  species,  Actinomyces israelii  and other  Actinomyces  species, and  Propionibacterium acnes.    
     
     
         66 . The method of  claim 63 , wherein the bacterial infection is a gram negative bacterial infection. 
     
     
         67 . The method of  claim 66 , wherein the bacterial infection is selected from the group consisting of:  Clostridium tetani, Clostridium perfringens, Clostridium botulinum , other  Clostridium  species,  Pseudomonas aeruginosa , other  Pseudomonas  species,  Campylobacter species, Vibrio cholerae, Ehrlichia species, Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida , other  Pasteurella  species,  Legionella pneumophila , other  Legionella  species,  Salmonella typhi , other  Salmonella  species,  Shigella  species  Brucella abortus , other  Brucella  species,  Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi , other  Hemophilus  species,  Yersinia pestis, Yersinia enterolitica , other  Yersinia  species,  Escherichia coli, E. hirae  and other  Escherichia  species, as well as other Enterobacteriaceae,  Brucella abortus  and other  Brucella  species,  Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fusobascterium nucleatum, Provetella  species and  Cowdria ruminantium.    
     
     
         68 . The method of  claim 63 , wherein the compound does not affect tubulin. 
     
     
         69 . A method of inhibiting bacterial growth comprising contacting a bacterium with an effective amount of a compound having the structure 4-[(6-Amino-2,3-diphenyl-pyrido[2,3-b]pyrazin-8-ylamino)-methyl]-N,N-diethyl-benzenesulfonamide. 
     
     
         70 . A method of treating a subject with a bacterial infection, comprising administering to the subject an effective amount of one or more compounds having the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 a) X 1  and X 2  are CH or N, and at least one of X 1  and X 2  are N; 
 b) S 1  is an organic radical comprising 1 to 8 carbon atoms; 
 c) S 2 , S 3 , and S 4  are independently selected from hydrogen, amino, halogen, or one or more organic radicals comprising 1 to 26 carbon atoms; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         71 . The method of  claim 70 , wherein the bacterial infection is a gram positive bacterial infection. 
     
     
         72 . The method of  claim 71 , wherein the bacterial infection is selected from the group consisting of:  M. tuberculosis, M. bovis, M. typhimurium, M. bovis  strain BCG, BCG substrains,  M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium  subspecies  paratuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus equi, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Listeria ivanovii, Bacillus anthracis, B. subtilis, Nocardia asteroides , and other  Nocardia  species,  Streptococcus  viridans group,  Peptococcus  species,  Peptostreptococcus  species,  Actinomyces israelii  and other  Actinomyces  species, and  Propionibacterium acnes.    
     
     
         73 . The method of  claim 70 , wherein the bacterial infection is a gram negative bacterial infection. 
     
     
         74 . The method of  claim 73 , wherein the bacterial infection is selected from the group consisting of:  Clostridium tetani, Clostridium perfringens, Clostridium botulinum , other  Clostridium  species,  Pseudomonas aeruginosa , other  Pseudomonas  species,  Campylobacter  species,  Vibrio cholerae, Ehrlichia  species,  Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida , other  Pasteurella  species,  Legionella pneumophila , other  Legionella  species,  Salmonella typhi , other  Salmonella  species,  Shigella  species  Brucella abortus , other  Brucella  species,  Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi , other  Hemophilus  species,  Yersinia pestis, Yersinia enterolitica , other  Yersinia  species,  Escherichia coli, E. hirae  and other  Escherichia  species, as well as other Enterobacteriacae,  Brucella abortus  and other  Brucella  species,  Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fusobascterium nucleatum, Provetella  species and  Cowdria ruminantium.    
     
     
         75 . The method of  claim 70 , wherein the compound does not inhibit tubulin polymerization.