Transcription factor modulating compounds and methods of use thereof

Abstract

Substituted benzoimidazole compounds useful as anti-infectives that decrease resistance, virulence, or growth of microbes are provided. Methods of making and using substituted benzoimidazole compounds, as well as pharmaceutical preparations thereof, in, e.g., reducing antibiotic resistance and inhibiting biofilms.

1 . A method for reducing virulence of a microbial cell, comprising contacting said cell with a transcription factor modulating compound of the formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R 1  is OH, OCOCO 2 H, or a substituted or unsubstituted straight or branched C 1 -C 5  alkyloxy group; 
 R 2  is H, CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and 
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of H, (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), C(NOH)(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO 2 H, CN, NO 2 , CONH 2 , (CO)(NHOH), and halogen; 
 provided that when R 6  is NO 2  and R 2  is unsubstituted phenyl, then R 1  is not O(CHCH 3 )(CO 2 )CH 2 CH 3  or OCH 2 CO 2 H; 
 provided that when R 6  is H or NO 2 , then R 1  is not a phenyl-substituted alkyloxy group; 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is para-methoxyphenyl, then R 1  is not OH; and 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is unsubstituted phenyl, then R 1  is not OCH 2 CO 2 CH 2 CH 3 ; such that the virulence of said cell is reduced. 
 
       
     
     
         2 - 19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a transcription factor modulating compound, wherein said compound is of the formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R 1  is OH, OCOCO 2 H, or a substituted straight or branched C 1 -C 5  alkyloxy group, provided that R 1  is not a 2-amino-substituted ethoxy group or a substituted or unsubstituted benzyloxy group; 
 R 2  is H, CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group, provided that said aryl group is not a thiazolyl or isothiazolyl group; and 
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of H, (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), C(NOH)(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO 2 H, CN, NO 2 , CONH 2 , (CO)(NHOH), and halogen; 
 provided that when R 6  is NO 2  and R 2  is unsubstituted phenyl, then R 1  is not O(CHCH 3 )(CO 2 )CH 2 CH 3  or OCH 2 CO 2 H; 
 provided that when R 6  is H or NO 2 , then R 1  is not a phenyl-substituted alkyloxy group; 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is para-methoxyphenyl, then R 1  is not OH; and 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is unsubstituted phenyl, or when R 4 , R 5 , and R 7  are all H, R 6  is Cl, and R 2  is para-methyl-phenyl, then R 1  is not OCH 2 CO 2 CH 2 CH 3 ; or pharmaceutically acceptable salts thereof. 
 
       
     
     
         21 - 39 . (canceled) 
     
     
         40 . A method of treating medical indwelling devices comprising administering a composition comprising a transcription factor modulating compound of the formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R 1  is OH, OCOCO 2 H, or a substituted or unsubstituted straight or branched C 1 -C 5  alkyloxy group; 
 R 2  is H, CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and 
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of H, (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), C(NOH)(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO 2 H, CN, NO 2 , CONH 2 , (CO)(NHOH), and halogen; 
 provided that when R 6  is NO 2  and R 2  is unsubstituted phenyl, then R 1  is not O(CHCH 3 )(CO 2 )CH 2 CH 3  or OCH 2 CO 2 H; 
 provided that when R 6  is H or NO 2 , then R 1  is not a phenyl-substituted alkyloxy group; 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is para-methoxyphenyl, then R 1  is not OH; and 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is unsubstituted phenyl, then R 1  is not OCH 2 CO 2 CH 2 CH 3 ; such that said medical indwelling devices are treated. 
 
       
     
     
         41 - 47 . (canceled) 
     
     
         48 . A method for preventing infection of a subject by a microbe, comprising administering to said subject an effective amount of a transcription factor modulating compound of the formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R 1  is OH, OCOCO 2 H, or a substituted or unsubstituted straight or branched C 1 -C 5  alkyloxy group; 
 R 2  is H, CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and 
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of H, (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), C(NOH)(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO 2 H, CN, NO 2 , CONH 2 , (CO)(NHOH), and halogen; 
 provided that when R 6  is NO 2  and R 2  is unsubstituted phenyl, then R 1  is not O(CHCH 3 )(CO 2 )CH 2 CH 3  or OCH 2 CO 2 H; 
 provided that when R 6  is H or NO 2 , then R 1  is not a phenyl-substituted alkyloxy group; 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is para-methoxyphenyl, then R 1  is not OH; and 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is unsubstituted phenyl, then R 1  is not OCH 2 CO 2 CH 2 CH 3 ; 
 
         such that the infection prevented. 
       
     
     
         49 . The method of  claim 48 , wherein said subject is a human. 
     
     
         50 . The method of  claim 48 , wherein said transcription factor modulating compound is a MarA family polypeptide inhibitor or a AraC family polypeptide inhibitor. 
     
     
         51 - 57 . (canceled) 
     
     
         58 . A compound of formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R 1  is OH, OCOCO 2 H, or a substituted or unsubstituted straight or branched C 1 -C 5  alkyloxy group; 
 R 2  is H, CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and 
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of H, (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO 2 (C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), C(NOH)(C 1 -C 5  substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO 2 H, CN, NO 2 , CONH 2 , (CO)(NHOH), and halogen; 
 provided that when R 6  is NO 2  and R 2  is unsubstituted phenyl, then R 1  is not O(CHCH 3 )(CO 2 )CH 2 CH 3  or OCH 2 CO 2 H; 
 provided that when R 6  is H or NO 2 , then R 1  is not a phenyl-substituted alkyloxy group; 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is para-methoxyphenyl, then R 1  is not OH; and 
 provided that when R 4 , R 5 , R 6 , and R 7  are all H and R 2  is unsubstituted phenyl, then R 1  is not OCH 2 CO 2 CH 2 CH 3 , and pharmaceutically acceptable salts thereof. 
 
       
     
     
         59 . The method of  claim 1 , wherein microbe is selected from the group consisting of consisting of  Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia  cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Yibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group,  Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus  subsp.  hyicus, Staphylococcus haemolyticus, Staphylococcus hominis , and  Staphylococcus saccharolyticus.    
     
     
         60 . The method of  claim 48 , wherein said microbe is selected from the group consisting of consisting of  Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella  haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Yibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group,  Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus  subsp.  hyicus, Staphylococcus haemolyticus, Staphylococcus hominis , and  Staphylococcus saccharolyticus.    
     
     
         61 . The method of  claim 48 , wherein said subject is at risk of suffering from an infection. 
     
     
         62 . The method of  claim 1 , further comprising the step of administering the transcription factor modulating compound to a subject. 
     
     
         63 . The method of  claim 62 , wherein said subject is at risk of developing an infection with the microbe. 
     
     
         64 . The composition of  claim 20 , wherein said transcription factor modulating compound reduces microbial virulence. 
     
     
         65 . The composition of  claim 20 , wherein said composition further comprises an antibiotic.