Substituted 2-aminobenzimidazoles analogs as antibiofilm agents

Abstract

In one aspect, the disclosure relates to compositions and methods for dispersing exiting Salmonella biofilms and inhibiting formation of Salmonella biofilms. In various aspects, the disclosed compositions can be used in methods of treating a persistent Salmonella infection, including an asymptomatic infection. Such infections can colonize a variety of tissues, including the gall-bladder. Also disclosed are methods of treating typhoid fever. Also disclosed are methods for mitigating or preventing secondary outbreaks of typhoid fever by treating asymptomatic subjects who had been symptomatic for typhoid fever at a previous time. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

1 . A pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from a C1-C12 alkyl, a C3-C12 cycloalkyl; and a substituted aryl; and 
         wherein R 2  is selected from a C1-C12 alkyl, a C3-C12 cycloalkyl; and a substituted aryl; 
         or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R 1  is selected from a C1-C12 alkyl and a substituted aryl. 
     
     
         3 . The pharmaceutical composition of claim  0 , wherein R 1  is a C1-C12 alkyl. 
     
     
         4 . The pharmaceutical composition of claim  0 , wherein R 1  is a C1-C6 alkyl. 
     
     
         5 . The pharmaceutical composition of claim  0 , wherein R 1  is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, 3,3-dimethylbutan-2-yl, and 2,3-dimethylbutan-2-yl. 
     
     
         6 . The pharmaceutical composition of claim  0 , wherein R 1  is a substituted aryl. 
     
     
         7 . The pharmaceutical composition of claim  0 , wherein R 1  is a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, provided that at least one of R 10a , R 10b , R 10c , R 10d  and R 10e  is not hydrogen. 
       
     
     
         8 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d , R 10e  is independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, provided that two R 10a , R 10b , R 10c , R 10d  and R 10e  are hydrogen. 
     
     
         9 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy, provided that at least one of R 10a , R 10b , R 10c , R 10d  and R 10e  is not hydrogen. 
     
     
         10 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy, provided that at least one of R 10a , R 10b , R 10c , R 10d  and R 10e  is not hydrogen. 
     
     
         11 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, bromo, and chloro, provided that at least one of R 10a , R 10b , R 10c , R 10d  and R 10e  is not hydrogen. 
     
     
         12 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, bromo, and chloro, provided that two of R 10a , R 10b , R 10c , R 10d  and R 10e  are hydrogen. 
     
     
         13 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d  and R 10e  is independently selected from hydrogen, bromo, and chloro, provided that three of R 10a , R 10b , R 10c , R 10d  and R 10e  are hydrogen. 
     
     
         14 . The pharmaceutical composition of claim  0 , wherein each of R 10a , R 10b , R 10c , R 10d , R 10e  is independently selected from hydrogen, bromo, and chloro, provided that four of R 10a , R 10b , R 10c , R 10d  and R 10e  are hydrogen. 
     
     
         15 . The pharmaceutical composition of claim  0 , wherein R 1  is a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 10b  and R 10c  is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. 
       
     
     
         16 - 19 . (canceled) 
     
     
         20 . The pharmaceutical composition of claim  0 , wherein R 1  is a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 10b  and R 10d  is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. 
       
     
     
         21 - 24 . (canceled) 
     
     
         25 . The pharmaceutical composition of claim  0 , wherein R 1  is a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 10c  is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. 
       
     
     
         26 - 29 . (canceled) 
     
     
         30 . The pharmaceutical composition of  claim 1 , present as: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a subgroup thereof. 
       
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method for treating a  Salmonella enterica  clinical condition, comprising administering to a subject in need thereof the pharmaceutical composition of  claim 1 . 
     
     
         34 - 45 . (canceled) 
     
     
         46 . A method for inhibiting biofilm formation or dispersing a biofilm in a subject comprising the step of administering to the subject the pharmaceutical composition of  claim 1 . 
     
     
         47 - 58 . (canceled)