Antimicrobial agents and uses thereof

Abstract

The invention features compounds that act as antimicrobial agents and/or antimicrobial enhancer agents, compositions that include the antimicrobial enhancer agents of the invention, and methods for treating microbial infections using those compositions.

1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein a 1  and a 2  combine to form a fused ring described by formulas:  
       
         
           
           
               
               
           
         
       
       X 1  represents a sulfur atom; 
 R 1  represents H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, aryl, or heteroalkyl;  
 R 2  represents OR 3 , SR 3 , a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;  
 each R 3 , independently, represents H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, acyl, aryl, heteroalkyl, S(O) 1-2 —C 1-6  alkyl, S(O) 1-2 -aryl, S(O) 1-2 —C 2-6  alkenyl, or S(O) 1-2 —C 2-6 -alkynyl;  
 and R 4  represents a group expressed by the formula:  
                     
 wherein each of R 5  and R 6  is, independently, an alkyl group having 1 to 7 carbon atoms, or R 5  and R 6  combine to form a 3-8 membered cyclic system,  
 or R 4  represents a group expressed by the formula:  
                     
 in which g represents an integer between 1 and 3; or R 4  represents a group expressed by the formula:  
                     
 wherein each of R 7  and R 8  is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and X 2  represents an oxygen atom, a sulfur atom, a carbonyl group,  
 or X 2  represents a group expressed by the formula:  
                     
 in which each of R 9  and R 10  is, independently, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms, or R 9  and R 10 , in combination with each other, represent —(CH 2 ) k — in which k represents an integer between 1 and 4;  
 or X 2  represents a group expressed by the formula:  
                     
 in which m represents 0 or 1, R 11  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3  in which n represents an integer between 1 and 4, and X 3  represents a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group,  
 or X 2  represents a group expressed by the formula:  
                     
 
     
     
         2 . The compound of  claim 1 , wherein said compound is of formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, aryl, or heteroalkyl;  
 R 2  represents OR 3 , SR 3 , a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;  
 Each R 3 , independently, represents C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, acyl, aryl, heteroalkyl, S(O) 1-2 —C 1-6  alkyl, S(O) 1-2 -aryl, S(O) 1-2 —C 2-6  alkenyl, or S(O) 1-2 —C 2-6 -alkynyl;  
 each of R 7  and R 8  is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;  
 and X 2  represents a group expressed by the formula:  
                     
 in which m represents 0 or 1, and R 11  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3  in which n represents an integer between 1 and 4, and X 3  represents a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group.  
 
     
     
         3 . The compound of  claim 1 , wherein said compound is of formula III:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, aryl, or heteroalkyl;  
 R 2  represents OR 3 , SR 3 , a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;  
 each R 3 , independently, represents C 1-6  alkyl, C 2-6  alkenyl, C 2 - 6 -alkynyl, acyl, aryl, heteroalkyl, S(O) 1-2 —C 1-6  alkyl, S(O) 1-2 -aryl, S(O) 1-2 —C 2-6  alkenyl, or S(O) 1-2 —C 2-6 -alkynyl;  
 each of R 7  and R 8  is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;  
 and X 2  represents a group expressed by the formula:  
                     
 in which m represents 0 or 1, and R 11  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3  in which n represents an integer between 1 and 4, and X 3  represents a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group.  
 
     
     
         4 . A compound of formula IV:  
       
         
           
           
               
               
           
         
       
       wherein X 1  represents an oxygen atom or a sulfur atom; 
 R 2  represents OR 3 , SR 3 , a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;  
 Each R 3 , independently, represents H, C 1-10  alkyl, C 2-10  alkenyl, S(O) 1-2 —C 1-10 -alkyl, S(O) 1-2 —C 1-10 -aryl, S(O) 1-2 —C 1-10 -heteroaryl, or S(O) 1-2 —C 1-10 -heterocyclyl;  
 each of R 7  and R 8  is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;  
 R 11  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3  in which n represents an integer between 1 and 4, and X 3  represents a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group;  
 R 12  is H, O, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, acyl, aryl, or heteroalkyl; and  
 R 13  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, acyl, aryl, heteroalkyl, OH, SH, OR 3 , or SR 3 .  
 
     
     
         5 . A compound of formula V:  
       
         
           
           
               
               
           
         
       
       V  
       wherein X 4  represents an oxygen atom or a sulfur atom; 
 R 2  represents OR 3 , SR 3 , a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms;  
 R 3  represents H, C 1-10  alkyl, C 2-10  alkenyl, S(O) 1-2 —C 1-10 -alkyl, S(O) 1-2 —C 1-10 -aryl, S(O) 1-2 —C 1-10 -heteroaryl, or S(O) 1-2 —C 1-10 -heterocyclyl;  
 each of R 7  and R 8  is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;  
 R 11  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3  in which n represents an integer between 1 and 4, and X 3  represents a halogen atom, an alkoxy group having 1 to 3 carbon atoms, a vinyl group, or an ethynyl group;  
 R 14  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, aryl, or heteroalkyl; and  
 R 15  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6 -alkynyl, acyl, aryl, or heteroalkyl.  
 
     
     
         6 . A method of treating an infection of microbes selected from bacteria, fungi, and protozoans, or killing said microbes, said method comprising contacting said microbe or a site susceptible to microbial growth with a compound of  claim 1 ,  4 , or  5  in an amount sufficient to treat or kill the microbes.  
     
     
         7 . The method of  claim 6 , wherein contacting said microbes comprises administering said compound to a mammal in an amount effective to treat a microbial infection  
     
     
         8 . The method of  claim 7 , wherein said compound of  claim 1 ,  4 , or  5  is administered in parallel with one or more antifungal agents, antibacterial agents, or antiprotozoan agents, or combinations thereof.  
     
     
         9 . A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, said method comprising: 
 a. contacting the microbe with the antimicrobial agent; and    b. contacting the microbe with a compound of  claim 1 ,  4 , or  5  in an amount effective to increase the antimicrobial activity of the antimicrobial agent.    
     
     
         10 . A method of treating a disease associated with a bacterial infection in a patient, said method comprising administering to said patient a compound of  claim 1 ,  4 , or  5  in an amount sufficient to treat said disease.  
     
     
         11 . The method of  claim 10 , wherein said disease is an inflammatory disease.  
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 ,  4 ,  5 , or a suitable salt thereof, together with a pharmaceutically acceptable carrier or diluent.