US2009131401A1PendingUtilityA1
Transcription factor modulating compounds and methods of use thereof

Assignee: PARATEK PHARM INNCPriority: May 4, 2001Filed: Feb 12, 2008Published: May 21, 2009
Est. expiryMay 4, 2021(expired)· nominal 20-yr term from priority
Inventors:Stuart B. Levy Michael N. Alekshun Brent L. Podlogar Kwasi Ohemeng Atul K. Verma Tadeusz Warchol Beena Bhatia Todd Bowser Mark Grier
A61P 31/04A61P 31/00A61K 31/495A61K 31/415A61K 31/535A61K 31/425A61K 31/50A61K 31/42A61K 31/41A61K 31/407A61K 31/4745A61K 31/555A61K 31/47A61K 31/40A61K 31/505A61K 31/44A61K 31/55Y02A50/30
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References
Claims
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.
Claims

exact text as granted — not AI-modified
1 . A method for reducing antibiotic resistance 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 antibiotic resistance of said cell is reduced. 
 
     
     
         2 . A method for modulating a transcription, comprising contacting a transcription factor 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 transcription is modulated. 
 
     
     
         3 . The method of  claim 1  or  2 , wherein R 4 , R 5 , and R 7  are all H. 
     
     
         4 . The method of  claim 1  or  2 , wherein R 1  is selected from the group consisting of OH, O(CR′R″) 1-3 H, O(CR′R″) 1-3 OH, O(CR′R″) 1-3 CO 2 H, O(CR′R″) 1-3 CO 2 (CR′R″) 1-3 H, O(CR′R″) 1-3 (CO)NH 2 , O(CR′R″) 1-3 (CNH)NH 2 , OCOCO 2 H, O(CR′R″) 1-3 SO 3 H, O(CR′R″) 1-3 OSO 3 H, O(CR′R″) 1-3 PO 3 H, O(CR′R″) 1-3 OPO 3 H, O(CR′R″) 1-3 N[(CR′R″) 0-3 H] 2 , O(CR′R″) 1-3 (CO)(NHOH), and O(CR′R″) 1-3 (heteroaryl);
 wherein R′ and R″ are each independently H, a C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl group.   
     
     
         5 . The method of  claim 4 , wherein each R′ and R″ is independently H or CH 3 . 
     
     
         6 . The method of  claim 4 , wherein R 1  is O(CR′R″) 1-3 (heteroaryl), and wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         7 . The method of  claim 1  or  2 , wherein R 2  is a substituted or unsubstituted phenyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         8 . The method of  claim 3 , wherein R 6  is H, (CR′R″) 1-3 H, (CR′R″) 1-3 OH, (CR′R″) 1-3 NH 2 , (NOH)(CR′R″) 1-3 H, CO(CR′R″) 0-3 NH 2 , CO(CR′R″) 1-3 H, CO(CR′R″) 1-3 OH, CO(CR′R″) 1-3 CF 3 , (CR′R″) 1-3 N[(CR′R″) 0-3 H] 2 , CO(substituted or unsubstituted heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(CR′R″) 1-3 H, CO(substituted or unsubstituted phenyl), CO 2 (CR′R″) 1-3 H, CN, NO 2 , F, Cl, Br, or I,
 wherein R′ and R″ are each independently H, a C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl group.   
     
     
         9 . The method of  claim 8 , wherein each R′ and R″ is independently H or CH 3 . 
     
     
         10 . The method of  claim 8 , wherein R 6  is CO(substituted or unsubstituted heteroaryl), and wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         11 . The method of  claim 1  or  2 , wherein said transcription factor is a helix-turn-helix protein. 
     
     
         12 . The method of  claim 1  or  2 , wherein said transcription factor is a transcriptional activation factor. 
     
     
         13 . The method of  claims 12 , wherein said transcriptional activation factor is an AraC family polypeptide. 
     
     
         14 . The method of  claim 12 , wherein said transcriptional activation factor is a MarA family polypeptide. 
     
     
         15 . The method of  claim 1  or  2 , wherein said transcription factor modulating compound is a transcription factor inhibiting compound. 
     
     
         16 . The method of  claim 1  or  2 , wherein said transcription factor is prokaryotic. 
     
     
         17 . The method of  claim 14 , wherein said MarA family polypeptide is MarA, SoxS, or Rob. 
     
     
         18 . The method of  claim 1 , wherein said microbial cell is selected from the group consisting of  Pseudomonas aeruginosa, Pseudomonasfluorescens, 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.    
     
     
         19 . The method of  claim 1  or  2 , wherein said compound is a compound of Table 6 or Table 7. 
     
     
         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 . The pharmaceutical composition of  claim 20 , wherein R 4 , R 5 , and R 7  are all H. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein R 1  is selected from the group consisting of OH, O(CR′R″) 1-3 H, O(CR′R″) 1-3 H, O(CR′R″) 1-3 CO 2 H, O(CR′R″) 1-3 CO 2 (CR′R″) 1-3 H, O(CR′R″) 1-3 (CO)NH 2 , O(CR′R″) 1-3 (CNH)NH 2 , OCOCO 2 H, O(CR′R″) 1-3 SO 3 H, O(CR′R″) 1-3 OSO 3 H, O(CR′R″) 1-3 PO 3 H, O(CR′R″) 1-3 OPO 3 H, O(CR′R″) 1-3 N[(CR′R″) 0-3 H] 2 , O(CR′R″) 1-3 (CO)(NHOH), and O(CR′R″) 1-3 (heteroaryl);
 wherein R′ and R″ are each independently H, a C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl group.   
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein each R′ and R″ is independently H or CH 3 . 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein R 1  is O(CR′R″) 1-3 (heteroaryl), and wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         25 . The pharmaceutical composition of  claim 20 , wherein R 2  is a substituted or unsubstituted phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         26 . The pharmaceutical composition of  claim 20 , wherein R 6  is H, (CR′R″) 1-3 H, (CR′R″) 1-3 OH, (CR′R″) 1-3 NH 2 , (NOH)(CR′R″) 1-3 H, CO(CR′R″) 0-3 NH 2 , CO(CR′R″) 1-3 H, CO(CR′R″) 1-3 OH, CO(CR′R″) 0-3 CF 3 , (CR′R″) 0-3 N[(CR′R″) 0-3 H] 2 , CO(substituted or unsubstituted heteroaryl), CO(C 3 -C 6  substituted or unsubstituted cycloalkyl), O(CR′R″) 1-3 H, CO(substituted or unsubstituted phenyl), CO 2 (CR′R″) 0-3 H, CN, NO 2 , F, Cl, Br, or I,
 wherein R′ and R″ are each independently H, a C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl group.   
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein each R′ and R″ is independently H or CH 3 . 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein R 6  is CO(substituted or unsubstituted heteroaryl), wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group. 
     
     
         29 . The pharmaceutical composition of  claim 20 , further comprising an antibiotic. 
     
     
         30 . A pharmaceutical composition of  claim 20 , wherein said effective amount is effective to treat a biofilm associated state in said subject. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein said biofilm associated state is selected from the group consisting of middle ear infections, cystic fibrosis, osteomyelitis, acne, dental cavities, endocarditis, and prostatitis. 
     
     
         32 . The pharmaceutical composition of  claim 20 , wherein said compound is a compound of Table 6 or Table 7. 
     
     
         33 . A method of inhibiting a biofilm, comprising administering a composition comprising a transcription factor modulating compound of the formula 
       
         
           
           
               
               
           
         
       
       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 biofilm is inhibited. 
 
     
     
         34 . The method of  claim 33 , wherein said transcription factor modulating compound is a compound of Table 6 or Table 7. 
     
     
         35 . The method of  claim 33 , wherein said composition further comprises a surfactant. 
     
     
         36 . The method of  claim 35 , wherein said surfactant is Sodium Dodecyl Sulfate; Quaternary Ammonium Compounds; alkyl pyridinium iodides; Tween 80, Tween 85, Triton X 100; Brij 56; biological surfactants; Rhamnolipid, Surfactin, Visconsin, or sulfonates. 
     
     
         37 . The method of  claim 36 , wherein said biofilm development is diminished by the administration of said composition. 
     
     
         38 . A method of inhibiting the formation of a biofilm, comprising administering 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 formation of said biofilm is inhibited. 
 
     
     
         39 . A method for cleaning and disinfecting contact lenses comprising administering a composition comprising an acceptable carrier and 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 contact lenses are cleaned and disinfected. 
 
     
     
         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 1 , 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 2  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 . The method of  claim 40 , wherein said device is selected from the group consisting of catheters, orthopedic devices and implants. 
     
     
         42 . A method for treating or preventing a biofilm associated state in a subject, 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 1 , 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 biofilm associated state in said subject is treated. 
 
     
     
         43 . The method of  claim 42 , wherein said biofilm associated state is selected from the group consisting of middle ear infections, cystic fibrosis, osteomyelitis, acne, dental cavities, endocarditis, and prostatitis. 
     
     
         44 . The method of  claim 42 , further comprising administering a pharmaceutically acceptable carrier. 
     
     
         45 . The method of  claim 42 , wherein said subject is a mammal. 
     
     
         46 . The method of  claim 42 , wherein said mammal is a human. 
     
     
         47 . The method of  claim 42 , wherein said subject is immunocompromised. 
     
     
         48 . A method for preventing a bacterial associated state in a subject, 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 2  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 bacterial associated state in said subject is 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. 
     
     
         51 . The method of  claim 48 , wherein said transcription factor modulating compound is a AraC family polypeptide inhibitor. 
     
     
         52 . A method for reducing antibiotic resistance of a microbial cell, comprising contacting said cell with a transcription factor modulating compound of Table 8, such that the antibiotic resistance of said cell is reduced. 
     
     
         53 . A method for modulating a transcription, comprising contacting a transcription factor with a transcription factor modulating compound of Table 8, such that transcription is modulated. 
     
     
         54 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a transcription factor modulating compound, wherein said compound is of Table 8. 
     
     
         55 . A method of inhibiting the formation of a biofilm, comprising administering a transcription factor modulating compound of Table 8, such that a biofilm is inhibited. 
     
     
         56 . A method for preventing a bacterial associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of Table 8. such that a bacterial associated state is prevented. 
     
     
         57 . A method for treating or preventing a biofilm associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of Table 8, such that said biofilm associated state is treated or prevented. 
     
     
         58 . A compound of Table 6, Table 7, or Table 8.
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