Small molecule inhibitors of botulinum neurotoxins

Abstract

The invention provides potent quinolinol-based BoNT/A small-molecule inhibitors of botulinum neurotoxins, in particular of Clostridium botulinum serotype A neurotoxins. The invention also provides methods of using these small-molecule inhibitors to inhibit infections by Clostridium botulinum , as well as, methods of preventing infections by Clostridium botulinum through materials that may be ingested.

1 . A composition having Formula 1: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3 , being the same or different, are each selected from the group consisting of a H, a C 1  to C6 straight or branched alkyl group, an aryl group, a halogen, NR 5 R 6 , NO 2 , CH 2  CH 2 OH, CHO, COOH, CN, SO 3 H, and SO 2 NR 7 R 8 ; 
         wherein R 5 , R 6 , R 7  and R 8  being the same or different, are each selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group; 
         wherein R 4  is selected from the group consisting of a straight or branched alkyl group and an aryl group; 
         wherein Ar 1  is selected from the group consisting of 5- or 6-membered aromatic rings, 5- or 6-membered heteroaromatic rings, polycyclic aromatic ring systems, and heteroaromatic ring systems; 
         wherein X is selected from the group consisting of a O, OCH 2 , S, SCH 2 , NR 9 , NR 9 CH 2 , NR 9 CO, and CH 2 ; and 
         wherein R 9  is selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group. 
       
     
     
         2 . The composition of  claim 1  wherein the halogen is selected from the group consisting of F, Cl, Br, and I. 
     
     
         3 . The composition of  claim 1  wherein the aryl group is a phenyl, biphenyl, thiophenyl, or indolyl ring. 
     
     
         4 . The composition of  claim 1  further comprising a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant. 
     
     
         5 . The composition of  claim 1 , which further includes a pharmaceutically acceptable salt of the compound of Formula 1. 
     
     
         6 . A method of inhibiting a botulinum neurotoxin in a subject comprising administering to the subject a composition comprising at least one compound of Formula 1 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3 , being the same or different, are each selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, an aryl group, a halogen, NR 5 R 6 , NO 2 , CH 2 OH, CHO, COOH, CN, SO 3 H, and SO 2 NR 7 R 8 ; 
         wherein R 5 , R 6 , R 7 , and R 8 , being the same or different, are each selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group; 
         wherein R 4  is selected from the group consisting of a straight or branched alkyl group and an aryl group; 
         wherein Ar 1  is selected from the group consisting of 5- or 6-membered aromatic rings, 5- or 6-membered heteroaromatic rings, polycyclic aromatic ring systems, and heteroaromatic ring systems; 
         wherein X is selected from the group consisting of a O, OCH 2 , S, SCH 2 , NR 9 , NR 9 CH 2 , NR 9 CO, and CH 2 ; and 
         wherein R 9  is selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group. 
       
     
     
         7 . The method of  claim 6  wherein the composition includes two or more compounds of Formula 1. 
     
     
         8 . The method of  claim 6  wherein the composition includes a pharmaceutically acceptable salt of a compound of Formula 1. 
     
     
         9 . The method of  claim 6  wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant. 
     
     
         10 . The method of  claim 6  wherein the botulinum neurotoxin is a  Clostridium botulinum  serotype A neurotoxin, and inhibiting the botulinum neurotoxin inhibits or prevents a  Clostridium botulinum  infection. 
     
     
         11 . The method of  claim 6  wherein the subject is an animal. 
     
     
         12 . The method of  claim 6  wherein the subject is a human. 
     
     
         13 . A kit for treating a subject exposed to a botulinum neurotoxin comprising a composition with at least one compound of Formula 1 in a container, and instruction on administering the at least one compound, wherein Formula 1 comprises 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3 , being the same or different, are each selected from the group consisting of a H, a C 1  to C6 straight or branched alkyl group, an aryl group, a halogen, NR 5 R 6 , NO 2 , CH 2  CH 2 OH, CHO, COOH, CN, SO 3 H, and SO 2 NR 7 R 8 ; 
         wherein R 5 , R 6 , R 7  and R 8  being the same or different, are each selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group; 
         wherein R 4  is selected from the group consisting of a straight or branched alkyl group and an aryl group; 
         wherein Ar 1  is selected from the group consisting of 5- or 6-membered aromatic rings, 5- or 6-membered heteroaromatic rings, polycyclic aromatic ring systems, and heteroaromatic ring systems; 
         wherein X is selected from the group consisting of a O, OCH 2 , S, SCH 2 , NR 9 , NR 9 CH 2 , NR 9 CO, and CH 2 ; and 
         wherein R 9  is selected from the group consisting of a H, a C 1  to C 6  straight or branched alkyl group, and an aryl group. 
       
     
     
         14 . A composition having Formula 2 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of a O, S, Se, and NH; 
         wherein Y is selected from the group consisting of a CH or N; 
         wherein Ar 1  is selected from the group consisting of a monocyclic or bicyclic aromatic or heteroaromatic ring system, a biphenyl or bipyridyl ring system, a bridged biphenyl or bipyridyl ring system, wherein any ring system may be further substituted by one or more substitution selected from the group consisting of a halogen, NR 1 R 2 , OR 3 , SO 2 NR 4 R 5 , SR 6 , and R 7 ; and 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7 , being the same or different, are each selected from the group consisting of H, a C 1  to C 6  straight or branched chain or cycloalkyl ring, a C 1  to C 6  straight or branched chain acyl group, and an aryl group. 
       
     
     
         15 . A method of inhibiting a botulinum neurotoxin in a subject comprising administering to the subject a composition comprising at least one compound of Formula 2 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of a O, S, Se, and NH; 
         wherein Y is selected from the group consisting of a CH or N; 
         wherein Ar 1  is selected from the group consisting of a monocyclic or bicyclic aromatic or heteroaromatic ring system, a biphenyl or bipyridyl ring system, a bridged biphenyl or bipyridyl ring system, wherein any ring system may be further substituted by one or more substitution selected from the group consisting of a halogen, NR 1 R 2 , OR 3 , SO 2 NR 4 R 5 , SR 6 , and R 7 ; and 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7 , being the same or different, are each selected from the group consisting of H, a C 1  to C 6  straight or branched chain or cycloalkyl ring, a C 1  to C 6  straight or branched chain acyl group, and an aryl group. 
       
     
     
         16 . The method of  claim 15  wherein the botulinum neurotoxin is a  Clostridium botulinum  serotype A neurotoxin, and inhibiting the botulinum neurotoxin inhibits or prevents a  Clostridium botulinum  infection. 
     
     
         17 . The method of  claim 15 , wherein the composition includes two or more compounds of Formula 2. 
     
     
         18 . The method of  claim 15 , wherein the composition includes a pharmaceutically acceptable salt of a compound of Formula 2. 
     
     
         19 . The method of  claim 15 , wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant. 
     
     
         20 . A kit for treating a subject exposed to a botulinum neurotoxin comprising a composition with at least one compound of Formula 2 in a container, and instruction on administering the at least one compound, wherein Formula 2 comprises 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of a O, S, Se, and NH; 
         wherein Y is selected from the group consisting of a CH or N; 
         wherein Ar 1  is selected from the group consisting of a monocyclic or bicyclic aromatic or heteroaromatic ring system, a biphenyl or bipyridyl ring system, a bridged biphenyl or bipyridyl ring system, wherein any ring system may be further substituted by one or more substitution selected from the group consisting of a halogen, NR 1 R 2 , OR 3 , SO 2 NR 4 R 5 , SR 6 , and R 7 ; and 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7 , being the same or different, are each selected from the group consisting of H, a C 1  to C 6  straight or branched chain or cycloalkyl ring, a C 1  to C 6  straight or branched chain acyl group, and an aryl group.