Compositions and methods for inhibition of mycobacteria

Abstract

A composition comprising a drug selected from the group consisting of an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof, in an amount and formulation sufficient to inhibit a mycobacterium is disclosed.

1 . A composition comprising a drug selected from the group consisting of an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof, in an amount and formulation sufficient to inhibit a mycobacterium. 
     
     
         2 . The composition of  claim 1 , wherein the aryloxyphenoxyacetate derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from —OR 5 , —NR 6 R 7  and —NH—SO 2 —R 8  groups, 
         R 2  and R 3  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl groups; or R 2  and R 3  together are a cycloalkyl group; 
         R 4  is selected from the group consisting of aryl, heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionally additionally substituted with from zero to four substitutions selected independently from halogen, hydroxyl, alkyl, alkoxy, nitril, nitro, amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, acyl, carboxamido, alkylsulfoxide, acylamino, phenyl, benzyl, phenoxy, and benzyloxy groups; 
         R 5  is selected from hydrogen or an alkyl, aryl, or benzyl group that is optionally additionally substituted with an alkyloxy, alkylamino, dialkylamino, or acylamino group; 
         R 6  and R 7  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy groups; or R 6  and R 7  together are a cycloalkyl or heterocycloalkyl group; and 
         R 8  is an alkyl or aryl group optionally substituted with halogen. 
       
     
     
         3 . The composition of  claim 1 , wherein the aryloxyphenacetate derivative has the following formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from —OR 5 , —NR 6 R 7  and —NH—SO 2 —R 8  groups,
 R 2  and R 3  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl groups; or R 2  and R 3  together are a cycloalkyl group; 
 R 4  is selected from the group consisting of aryl, heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionally additionally substituted with from zero to four substitutions selected independently from halogen, hydroxyl, alkyl, alkoxy, nitril, nitro, amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, acyl, carboxamido, alkylsulfoxide, acylamino, phenyl, benzyl, phenoxy, and benzyloxy groups; 
 R 5  is selected from hydrogen or an alkyl, aryl, or benzyl group that is optionally additionally substituted with an alkyloxy, alkylamino, dialkylamino, or acylamino group; 
 R 6  and R 7  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy groups; or R 6  and R 7  together are a cycloalkyl or heterocycloalkyl group; and 
 R 8  is an alkyl or aryl group optionally substituted with halogen. 
 
 
       
     
     
         4 . The composition of  claim 1 , wherein the drug is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1 , wherein the substituted quinol has the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 9  is selected from nitril, hydroxyl, heterocycloaryl and alkyloxy groups; and 
         R 4  is selected from the group consisting of aryl, heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionally additionally substituted with from zero to four substitutions chosen independently from the group consisting of halogen, hydroxyl, alkyl, alkyloxy, nitril, nitro, amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, acyl, carboxamido, alkylsulfoxide, acylamino, phenyl, benzyl, phenoxy, and benzyloxy groups. 
       
     
     
         6 . The composition of  claim 1 , wherein the arylphenoxypropionate derivative is selected from the group consisting of haloxyfop, quizalofop-p, quizalofop-p-ethyl (IUPAC name: ethyl (2R)-2-[4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionate), fenoxaprop-p, fenoxaprop-p-ethyl, or proquizafop. 
     
     
         7 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier, a salt, a buffer, a preservative, or a solubility enhancer. 
     
     
         8 . The composition of  claim 1 , wherein the mycobacterium is  Mycobacterium tuberculosis  or  Mycobacterium bovis.    
     
     
         9 . A method of inhibiting a mycobacterium comprising: administering a composition comprising an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof to the mycobacterium in an amount and for a time sufficient to inhibit the mycobacterium. 
     
     
         10 . The method of  claim 9 , wherein the mycobacterium is pathogenic. 
     
     
         11 . The method of  claim 9 , wherein the mycobacterium is selected from the group consisting of  Mycobacterium tuberculosis  or  Mycobacterium bovis.    
     
     
         12 . The method of  claim 9 , wherein the composition is substantially nontoxic to animals. 
     
     
         13 . The method of  claim 9 , wherein the composition inhibits the mycobacterium by inhibiting AccD6. 
     
     
         14 . The method of  claim 9 , wherein the mycobacterium is drug resistant. 
     
     
         15 . The method of  claim 9 , wherein the mycobacterium is multi-drug resistant. 
     
     
         16 . The method of  claim 9 , wherein the arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof has a minimum inhibitory concentration of about 10 μM or less.