Small Molecule Inhibitors of Botulinum Neurotoxins

Abstract

Disclosed herein are methods of inhibiting the activity of Botulinum neurotoxin A metalloprotease with the compounds disclosed herein. Also disclosed are methods of treating, inhibiting or preventing intoxication caused by bacteria of at least one bacterial strain in a subject, and pharmaceutical and cosmetic compositions comprising the compounds disclosed herein.

1 . A method of inhibiting the activity of Botulinum neurotoxin A metalloprotease which comprises contacting Botulinum neurotoxin A metalloprotease with at least one compound having the following structural formula: 
       
         
           
           
               
               
           
         
         wherein
 n is 1 or 2; 
 
         X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are each independently N, S, O, SO 2 , CR 7  or NR 8  and at least one of X 1  or X 2  is N, S, O, SO 2 , or NR 8 ;
 L is a linker which may be a direct bond or 
 
       
       
         
           
           
               
               
           
         
       
       where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
   R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate; and   R 8  is hydrogen, OH, a halogen, or an optionally substituted alkyl.   
 
     
     
         2 . The method of  claim 1 , wherein at least one of R 1 , R 2 , R 3 , or R 4  is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine. 
     
     
         3 . The method of  claim 1 , wherein R 5  is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, methylamine-guanidine, 4-oxy-benzamidine, 1H-indole-6-caboxamidine, or 1H-indole-5-carboxamidine. 
     
     
         4 . The method of  claim 1 , wherein R 6  is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl-imidazoline, benzofuran-2-yl-amidine, benzofuran-2-yl-guanidine, benzothiophene-2-yl-imidazoline, benzothiophene-2-yl-amidine, benzene-2-yl-amidine, benzofuran-2-yl-imidazole, or benzofuran-2-yl-oxazole. 
     
     
         5 . The method of  claim 1 , wherein at least one of X 1  or X 2  is N, NH, S, O, SO 2 , CH, C—CH 3 , C-phenyl, N-ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5-amidine). 
     
     
         6 . The method of  claim 1 , wherein at least one of X 3 , X 4 , X 5 , or X 6  is N, NH, S, O, SO 2 , or CH. 
     
     
         7 . The method of  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is —H, —CH 3 ,— 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein R 5  is —NH 2 , 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein R 7  is —H, —CH 3 , —NH 2 , 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein R 8  is —H, —(CH 2 ) 2 OH, or —(CH 2 ) 2 Cl. 
     
     
         12 . The method of  claim 1 , wherein L is a direct bond, 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein the compound has the following structural formulae: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of inhibiting the activity of Botulinum neurotoxin A metalloprotease which comprises contacting Botulinum neurotoxin A metalloprotease with at least one compound selected from the group consisting of NSC 92833, NSC 103699, NSC 103701, NSC 130681, NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240896, NSC 240897, NSC 240898, NSC 240899, NSC 240900, NSC 266472, NSC 266474, NSC 266475, NSC 266476, NSC 266477, NSC 266482, NSC 278995, NSC 278996, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290109, NSC 290111, NSC 291103, NSC 294199, NSC 294200, NSC 294201, NSC 294202, NSC 294203, NSC 294204, NSC 294206, NSC 294207, NSC 294208, NSC 294494, NSC 300509, NSC 300510, NSC 300511, NSC 300512, NSC 302569, NSC 308569, NSC 308570, NSC 308571, NSC 308572, NSC 308573, NSC 308574, NSC 317880, NSC 317881, NSC 317883, NSC 317884, NSC 317885, NSC 317886, NSC 317887, NSC 328398, NSC 330687, NSC 330688, NSC 330689, NSC 330690, NSC 341082, NSC 341907, NSC 341909, NSC 341910, NSC 341911, NSC 352341, NSC 369718, NSC 369721, NSC 607617, and NSC 12155. 
     
     
         15 . The method of  claim 14 , wherein the compound is NSC 341909, NSC 308574, NSC 240898, NSC 341907, NSC 266472, NSC 330690, NSC 278999, NSC 308571, NSC 290107, NSC 290108, NSC 294200, NSC 317884, NSC 317884, NSC 294203, NSC 294494, NSC 317881, NSC 330688, NSC 317886, NSC 317833, NSC 328398 NSC 352341, NSC 294204, NSC 341911, NSC 300511, NSC 607617, NSC 294202, NSC 317880, NSC 240899, NSC 294201, NSC 291103, NSC 308573, NSC 290109, NSC 294206, NSC 308570, NSC 294199, NSC 369723, or NSC 300510. 
     
     
         16 . A method of treating, inhibiting or preventing a subject from being intoxicated by Botulinum toxin which comprises administering to the subject a therapeutically effective amount of at least one compound having the following structural formula: 
       
         
           
           
               
               
           
         
         wherein
 n is 1 or 2; 
 X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are each independently N, S, O, SO 2 , CR 7  or NR 8  and at least one of X 1  or X 2  is N, S, O, SO 2 , or NR 8 ; 
 L is a linker which may be a direct bond 
 
       
       
         
           
           
               
               
           
         
       
       or where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
   R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate; and   
 R 8  is hydrogen, OH, a halogen, or an optionally substituted alkyl. 
 
     
     
         17 . A compound having the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein R a  and R b  are each independently —CN, —CONH 2 , or —C(═NH)NH 2 ; X is —NH or O; and Y is N or —CH, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A method of inhibiting the activity of Botulinum neurotoxin A metalloprotease which comprises contacting Botulinum neurotoxin A metalloprotease with at least one compound of  claim 17 . 
     
     
         19 . A method of treating, inhibiting or preventing a subject from being intoxicated by Botulinum toxin which comprises administering to the subject a therapeutically effective amount of at least one compound of  claim 17 . 
     
     
         20 . A pharmaceutical composition comprising at least one compound of  claim 17  and a pharmaceutically acceptable carrier.