Antimicrobial compositions and methods of use thereof

Abstract

Described herein is a novel class of inhibitors of bacterial cell division. Several lines of evidence suggest the compounds disclosed herein specifically target the division process and have antibacterial activity in vitro and in vivo. The inhibitors are useful for treating subject in need of treatment for bacterial infections as will as for inhibiting bacterial growth, such as growth on contaminated surfaces.

1 . A pharmaceutical composition, comprising a cell division inhibitor and a pharmaceutically acceptable excipient, wherein the cell division inhibitor is of Formula I or a pharmaceutically acceptable salt thereof:
   G-Q-Y-Z-Ar   (I)
   
       wherein
 G is 
 
       
         
           
           
               
               
           
         
         wherein each instance of A is independently CH or N provided that the total number of N is 0 or 1; 
         R 1  is hydrogen, hydroxy, amino, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, or (aryl)alkyl; 
         X 1  is N, CR 2 , O, or S; 
         X 2  is O, S, or NR 4 ; 
         R 2  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, or (aryl)alkyl; 
         each instance of R 3  independently is hydroxy, sulfate, nitro, amino, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, phenyl, pyridyl, heterocycloalkyl, alkylcarboxamide, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; 
         n is 0, 1, or 2; 
         m is 0 or 1; 
         Q is a bond or a C 1 -C 6  hydrocarbon linking group comprising 0, 1, or 2 heteroatoms chosen from O, S, or NR 4 , and wherein the linking group is substituted by 0, 1, 2, or 3 substituents independently chosen from hydroxy, sulfate, nitro, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, or oxo; 
         R 4  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; 
         Y is —(C═O)NH—N═CH—, 
         —(C═O)NH—, 
         —NH(C═O)—, 
         —(C═O)O—, 
         —O(C═O)— 
         —O(C═O)O—, 
         —NH(C═O)NH—, 
         —NH(C═O)O—, 
         —O(C═O)NH— 
         or 
         —(C═O)—; 
         Z is a bond or a C 1 -C 3  hydrocarbon linking group comprising 0, 1, or 2 heteroatoms chosen from O, S, or NR 4 , and wherein the linking group is substituted by 0, 1, 2, or 3 substituents independently chosen from hydroxy, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, or oxo; 
         Ar is aryl or heteroaryl, substituted with 0, 1, 2, or 3 substituents independently chosen from hydroxy, sulfate, nitro, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, phenyl, pyridyl, heterocycloalkyl, alkylcarboxamide, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, and 
         the dashed line in the G structures is a single or double bond. 
       
     
     
         2 . The composition of  claim 1 , wherein R 1  is hydrogen, fluoro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, or aryl. 
     
     
         3 . The composition of  claim 2 , wherein R 1  is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy. 
     
     
         4 . The composition of  claim 3 , wherein R 1  is methyl or trifluoromethyl. 
     
     
         5 . The composition of  claim 4 , wherein X 1  is N. 
     
     
         6 . The composition of  claim 5 , wherein each instance of R 3  independently is hydroxy, sulfate, nitro, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 3 -0 5 cycloalkyl, mono- and di-(C 1 -C 2 alkyl)amino, C 2 -C 4 alkoxycarbonyl, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy. 
     
     
         7 . The composition of  claim 6 , wherein Q is a C 1 -C 3  hydrocarbon linking group substituted by 0, 1, 2, or 3 substituents independently chosen from hydroxy, amino, halogen, C 1 -C 2 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 22 alkoxy, mono- and di-(C 1 -C 2 alkyl)amino, C 2 -C 4 alkoxycarbonyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, or oxo. 
     
     
         8 . The composition of  claim 7 , wherein Y is —(C═O)NH—N═CH—, —(C═O)N—, —NH(C═O)NH—, —NH(C═O)O—, or —O(C═O)NH—. 
     
     
         9 . The composition of  claim 8 , wherein Z is a bond. 
     
     
         10 . The composition of  claim 9 , wherein Ar is aryl substituted with 1 or 2 substituents independently chosen from hydroxy, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy 
     
     
         11 . The composition of  claim 1 , wherein the inhibitor is of Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , X 1 , R 3 , n, Q, and Ar are as defined in  claim 1 . 
 
     
     
         12 . The composition of  claim 11 , wherein Ar is naphthalene substituted with a hydroxyl group or a methoxy group, or Ar is phenyl substituted with a hydroxy group. 
     
     
         13 . The composition of  claim 12 , wherein R 1  is H, CF 3  or CH 3 . 
     
     
         14 . The composition of  claim 13 , wherein Q is C 2 alkyl. 
     
     
         15 . The composition of  claim 14 , wherein the cell division inhibitor is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 - 25 . (canceled) 
     
     
         26 . The composition of  claim 1 , 
       wherein
 G is 
 
       
         
           
           
               
               
           
         
         wherein each instance of A is independently CH or N provided that the total number of N is 0 or 1; 
         R 1  is hydrogen, hydroxy, amino, halogen, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, or (aryl)alkyl; 
         X 1  is N, CR 2 , O, or S; 
         R 2  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, or (aryl)alkyl; 
         each instance of R 3  independently is hydroxy, sulfate, nitro, amino, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, phenyl, pyridyl, heterocycloalkyl, alkylcarboxamide, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; 
         n is 0, 1, or 2; 
         m is 0 or 1; 
         Q is a bond or a C 1 -C 6  hydrocarbon linking group comprising 0, 1, or 2 heteroatoms chosen from O, S, or NR 4 , and wherein the linking group is substituted by 0, 1, 2, or 3 substituents independently chosen from hydroxy, sulfate, nitro, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, or oxo; 
         R 4  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; 
         Y is —(C═O)NH—N═CH— or —(C═O)NH—; 
         Z is a bond or a C 1 -C 3  hydrocarbon linking group comprising 0, 1, or 2 heteroatoms chosen from O, S, or NR 4 ; 
         Ar is aryl substituted with 0, 1, 2, or 3 substituents independently chosen from hydroxy, sulfate, nitro, amino, cyano, halogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, phenyl, pyridyl, heterocycloalkyl, alkylcarboxamide, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; and 
         the dashed line in the G structures is a single or double bond. 
       
     
     
         27 . The composition of  claim 26 , wherein G is 
       
         
           
           
               
               
           
         
         wherein each instance of A is independently CH or N provided that the total number of N is 0 or 1; 
         R 1  is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 haloalkyl; 
         X 1  is N; 
         each instance of R 3  independently is a halogen; 
         n is 0, 1, or 2; 
         m is 0 or 1; 
         Q is a C 1 -C 6  hydrocarbon linking group; 
         Y is —(C═O)NH—N═CH—; 
         Z is a bond; 
         Ar is aryl substituted with 0, 1, 2, or 3 hydroxy; and 
         the dashed line in the G structures is a double bond. 
       
     
     
         28 . The composition of  claim 26 , wherein G is 
       
         
           
           
               
               
           
         
         wherein each instance of A is independently CH or N provided that the total number of N is 0 or 1; 
         R 1  is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 haloalkyl; 
         X 1  is N; 
         each instance of R 3  independently is a halogen; 
         n is 0, 1, or 2; 
         Q is a C 1 -C 6  hydrocarbon linking group; 
         Y is —(C═O)NH—N═CH—; 
         Z is a bond; 
         Ar is 1-naphthalenyl substituted with 0, 1, 2, or 3 hydroxy; and 
         the dashed line in the G structure is a double bond.