Compounds having antibacterial activity and methods of use

Abstract

In one aspect, methods of treating bacterial infections are described herein employing compounds having more than one target for antibacterial activity. Additionally, pharmaceutical compositions comprising such compounds are also described.

1 . A pharmaceutical composition comprising a compound of Formula (I) and/or salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 6   3 , and R 4  are independently selected from the group consisting of hydrogen and alkyl; 
         wherein R 2  is selected from the group consisting of aryl and heteroaryl; 
         wherein X and Z are independently selected from the group consisting of C, N and O; and; 
         wherein Y is selected from the group consisting of OH and NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein R 9  and R 10  may optionally form a ring structure; and n is an integer from 0 to 5; 
         wherein the compound of Formula (I) is present in the pharmaceutical composition at a concentration of 0.1 μg/ml to 100 μg/ml to induce membrane depolarization and/or membrane permeability in cells of a disease and/or disrupt a folate metabolic pathway in the cells of the disease. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (I) is present in the pharmaceutical composition at a concentration of 0.1 μg/ml to 10 μg/ml. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein R 2  is aryl. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the aryl is a multicyclic ring system. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein X and Z are C. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein R 9  and R 10  are hydrogen. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein R 1 , R 3 , R 4 , R 9  and, R 10  are each hydrogen, and X and Z are each C. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the aryl of R 2  is a multicyclic ring system. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the compound of Formula (I) is present in the pharmaceutical composition at a concentration of 0.1 μg/ml to 10 μg/ml. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the cells are bacteria cells. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the bacteria cells are gram negative. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the cells are cancer cells. 
     
     
         13 . A method of treating a disease in a patient comprising:
 inducing membrane depolarization and/or membrane permeability in cells of the disease; and   disrupting a folate metabolic pathway of the cells of the disease, wherein inducing the membrane depolarization and/or membrane permeability and disrupting the folate metabolic pathway is effectuated by administering to the patient a compound of Formula (I) and/or a salt thereof at a concentration of 0.1 μg/ml to 100 μg/ml:   
       
         
           
           
               
               
           
         
         wherein R 1 , R 3 , and R 4  are independently selected from the group consisting of hydrogen and alkyl; 
         wherein R 2  is selected from the group consisting of aryl and heteroaryl; 
         wherein X and Z are independently selected from the group consisting of C, N and O; and; 
         wherein Y is selected from the group consisting of OH and NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein R 9  and R 10  may optionally form a ring structure; and n is an integer from 0 to 5. 
       
     
     
         14 . The method of  claim 13 , wherein the concentration is 0.1 μg/ml to 10 μg/ml. 
     
     
         15 . The method of  claim 13 , wherein R 2  is aryl. 
     
     
         16 . The method of  claim 15 , wherein the aryl is a multicyclic ring system. 
     
     
         17 . The method of  claim 13 , wherein X and Z are C. 
     
     
         18 . The method of  claim 10 , wherein R 9  and R 10  are hydrogen. 
     
     
         19 . The method of  claim 15 , wherein R 1 , R 3 , R 4 , R 9  and, R 10  are each hydrogen, and X and Z are each C. 
     
     
         20 . The method of  claim 19 , wherein the aryl of R 2  is a multicyclic ring system. 
     
     
         21 . The method of  claim 20 , wherein the compound of Formula (I) is present in the pharmaceutical composition at a concentration of 0.1 μg/ml to 10 μg/ml. 
     
     
         22 . The method of  claim 13 , wherein the cells are bacteria cells. 
     
     
         23 . The method of  claim 22 , wherein the bacteria cells are gram negative. 
     
     
         24 . The method of  claim 13 , wherein the cells are cancer cells. 
     
     
         25 . The method of  claim 14 , wherein the cancer cells are breast cancer cells.