Antibacterials and/or modulators of biofilm formation and methods of using the same

Abstract

Amides substituted with aromatic groups were synthesized and some were purified to create enantiomer pure compounds. The compounds were tested to determine their ability to inhibit the growth of bacteria and the formation of biofilms created by bacteria. Some of these compounds were found to be effective antibacterials and to effectively inhibit the formation of biofilms.

We claim: 
     
         1 . A compound, comprising formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of: biphenyl, —(CH 2 ) n -biphenyl, biphenyl ketone, naphthalene, anthracene, benzyl optionally substituted with 1 to 3 halogens, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —NH 2 , —NO 2 , —CN, or —CF 3 , and phenyl optionally substituted with 1 to 3 halogens, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —NH 2 , —NO 2 , —CN, or —CF 3 ; 
 R 2  is selected from the group consisting of: —OH, —NH 2 , —NHR 3 , and —NR 3 R 4 ; 
 R 3  and R 4  are independently selected from the group consisting of: H, halogen, —NH 2 , —NO 2 , C 1 -C 6  alkyl being unbranched, branched or cyclic, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, hydroxyl, acyl, acyl amides, carboxyl, tetrazolyl, and —(CH 2 ) n —R 5 ; 
 alternatively, R 3  and R 4  are taken together to form a pyridine, a piperidine, a pyrrolidine, or a pyrrole ring; 
 R 5  is —OH, —CF 3 , morpholinyl, pyridinyl, benzyl optionally substituted with 1 to 3 halogens, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —NH 2 , —NO 2 , —CN, or —CF 3 , or phenyl optionally substituted with 1 to 3 halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —CN, or —CF 3 ; and 
 n is 1, 2, 3, or 4; 
 or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein:
 R 1  is benzyl substituted with 1 to 3 halogens, —NH 2 , —NO 2 , —CN, or —CF 3 ; and   R 2  is —OH or —NH 2 ;   or a pharmaceutically acceptable salt thereof, or a metabolite thereof.   
     
     
         3 . The compound according to  claim 1 , wherein:
 R 1  is benzyl substituted with 1 to 3 halogens, —NH 2 , —NO 2 , —CN, or —CF 3 ;   R 2  is —NHR 3 ;   R 3  is —(CH 2 ) n —R 5 ;   R 5  is —OH, —CF 3 , morpholinyl, pyridinyl, or benzyl optionally substituted with 1 to 3 halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —CN, or —CF 3 ; and   n is 1, 2, 3, or 4;   or a pharmaceutically acceptable salt thereof, or a metabolite thereof.   
     
     
         4 . The compound according to  claim 1 , wherein the compound is at least one enantiomer of at least one compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
       
     
     
         5 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
       
     
     
         6 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
       
     
     
         7 . A method for reducing the growth of bacteria, comprising the steps of:
 treating bacteria with at least one compound selected from the compounds of  claim 1 .   
     
     
         8 . The method according to  claim 7 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
       
     
     
         9 . The method according to  claim 7 , wherein the bacteria is gram-negative bacteria. 
     
     
         10 . The method according to  claim 7 , wherein the bacteria is  Pseudomonas aeruginosa.    
     
     
         11 . The method according to  claim 7 , further comprising the step of:
 reducing biofilm formation of the bacteria.   
     
     
         12 . The method according to  claim 7 , further comprising the step of:
 treating an area that has been infected by the bacteria.   
     
     
         13 . The method according to  claim 12 , wherein the area comprises surfaces or hair of an animal, a human, or a plant. 
     
     
         14 . A method of treating bacterial infections, comprising the steps of:
 providing at least one therapeutically effective dose of at least one compound selected from the compounds of  claim 1  to a patient.   
     
     
         15 . The method according to  claim 14 , further comprising the step of:
 diagnosing a patient with bacterial infections, wherein the bacterial infections are caused by gram-negative bacteria.   
     
     
         16 . The method according to  claim 15 , wherein the gram-negative bacteria is  Pseudomonas aeruginosa.    
     
     
         17 . The method according to  claim 14 , wherein the at least one compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a metabolite thereof. 
       
     
     
         18 . The method according to  claim 14 , wherein the therapeutically effective dose of the compound selected from the compounds of  claim 1  is on the order of between about 1 mg/kg to about 7 mg/kg and the dose of the compound is administered to the patient at least once per day. 
     
     
         19 . The method according to  claim 18 , wherein the therapeutically effective dose of the compound selected from the compounds of  claim 1  is on the order of between about 3 mg/kg to about 5 mg/kg and the dose of the compound is administered to the patient at least once per day. 
     
     
         20 . The method according to  claim 14 , wherein the therapeutically effective dose of the compound selected from the compounds of  claim 1  is administered by intravenous or intramuscular injections.