Modulation of pathogenicity

Abstract

The present invention relates to the use of compounds of the general Formula (I): wherein in Formula (I), R is H, alkyl, cycloalkyl, aryl or heteroaryl; R 1 is H, alkyl, cycloalkyl, aryl or heteroaryl; R 2 is H, alkyl, cycloalkyl, aryl or heteroaryl; A 1 and A 2 each independently represent an optionally substituted C 1 -C 20 -alkyl group which may contain one or more group(s) Z, or a monocyclic or polycyclic optionally substituted aromatic or non-aromatic ring system which may contain one or more group(s) X, and in case of a polycyclic ring system, said system contains at least one aromatic ring; Z is selected from the group consisting of S, O, N, NR 4 , CO, CO 2 , CS, SO or SO 2 X is selected from the group consisting of S, O, N, NR 4 , SO or SO 2 .

1 - 26 . (canceled) 
   
   
       27 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or physiologically functional derivative thereof, 
     wherein
 p is 0; 
 n is 0; 
 A 1  is thienyl, optionally substituted with one or more R 3 ; 
 Y 1  is —C(O)—, —C(S)—, or a bond; 
 R 1  is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 A 2  is (i) pyridyl, optionally substituted with one or more R 3 ; (ii) thienyl, optionally substituted with one or more R 3 ; or (iii) pyrrole, optionally substituted with one or more R 3 ; 
 each R 3  independently is OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkoxy, NO 2 , CN, SO 2 NR 4 R 5 , CO 2 NR 4 R 5 , COR 4 , CO 2 R 4 , SO 2 R 4 , SO 3 R 4 , NR 4 R 5 , alkyl, aryl, aryl substituted with halogen, or heteroaryl; 
 each R 4  independently is H, alkyl, cycloalkyl, aryl, or heteroaryl; and 
 each R 5  independently is H, O-alkyl, O-aryl, alkyl, heteroaryl, or aryl. 
 
   
   
       28 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or physiologically functional derivative thereof, 
     wherein
 p is 0; 
 n is 1; 
 A 1  is alkyl, aryl, or heteroaryl, each optionally substituted with one or more R 3 ; 
 Y 1  is —C(O)—, —C(S)—, or a bond; 
 R 1  is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 R 2  is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 Y 2  is —C(O)— or —C(S)—; 
 A 2  is thienyl, optionally substituted with one or more R 3 ; 
 each R 3  independently is OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkoxy, NO 2 , CN, SO 2 NR 4 R 5 , CO 2 NR 4 R 5 , COR 4 , CO 2 R 4 , SO 2 R 4 , SO 3 R 4 , NR 4 R 5 , alkyl, aryl, aryl substituted with halogen, or heteroaryl; 
 each R 4  independently is H, alkyl, cycloalkyl, aryl, or heteroaryl; and 
 each R 5  independently is H, O-alkyl, O-aryl, alkyl, heteroaryl, or aryl. 
 
   
   
       29 . The compound of  claim 28  wherein A 1  is alkyl, phenyl, pyrimidinyl, pyridinyl, furanyl, thienyl, benzothienyl, pyrrolopyridinyl, or 
     
       
         
         
             
             
         
       
     
     each of which may be optionally substituted with one or more R 3 . 
   
   
       30 . The compound of  claim 29  where R 3  is C 1-6  alkyl, C 1-6 alkoxy, halogen, C 1-6  haloalkyl, C 1-6  haloalkoxy, cycloalkyl, —CO 2 CH 3 , or —CO 2 CH 2 CH 3 . 
   
   
       31 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or physiologically functional derivative thereof, 
     wherein
 p is 1; 
 n is 1; 
 R is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 A 1  is alkyl, aryl, or heteroaryl, each optionally substituted with one or more R 3 ; 
 Y 1  is —C(O)—, —C(S)—, or a bond; 
 R 1  is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 R 2  is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ; 
 Y 2  is —C(O)— or —C(S)—; 
 A 2  is thienyl, optionally substituted with one or more R 3 ; 
 each R 3  independently is OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkoxy, NO 2 , CN, SO 2 NR 4 R 5 , CO 2 NR 4 R 5 , COR 4 , CO 2 R 4 , SO 2 R 4 , SO 3 R 4 , NR 4 R 5 , alkyl, aryl, aryl substituted with halogen, or heteroaryl; 
 each R 4  independently is H, alkyl, cycloalkyl, aryl, or heteroaryl; and 
 each R 5  independently is H, O-alkyl, O-aryl, alkyl, heteroaryl, or aryl. 
 
   
   
       32 . The compound of  claim 31  wherein A 1  is C 1-12  alkyl or phenyl, each optionally substituted with one or more R 3 . 
   
   
       33 . The compound of  claim 27  wherein A 1  is thienyl substituted with C 1-6  alkyl, halogen, or C 1-6  alkoxy. 
   
   
       34 . The compound of  claim 28  wherein A 2  is thienyl substituted with C 1-6  alkyl, halogen, or C 1-6  alkoxy. 
   
   
       35 . The compound of  claim 31  wherein A 2  is thienyl substituted with C 1-6  alkyl, halogen, or C 1-6  alkoxy. 
   
   
       36 . A method for inhibiting the production of a virulence factor comprising contact with a compound of  claim 27 . 
   
   
       37 . A method for inhibiting the production of a virulence factor comprising contact with a compound of  claim 28 . 
   
   
       38 . A method for inhibiting the production of a virulence factor comprising contact with a compound of  claim 31 . 
   
   
       39 . The method of  claim 36  for the treatment or prevention of bacterial damage or disease. 
   
   
       40 . The method of  claim 37  for the treatment or prevention of bacterial damage or disease. 
   
   
       41 . The method of  claim 38  for the treatment or prevention of bacterial damage or disease. 
   
   
       42 . The method of  claim 39  wherein the bacteria is  Pseudomonas aeruginosa  or  Burkholderia cepacia.    
   
   
       43 . The method of  claim 40  wherein the bacteria is  Pseudomonas aeruginosa  or  Burkholderia cepacia.    
   
   
       44 . The method of  claim 41  wherein the bacteria is  Pseudomonas aeruginosa  or  Burkholderia cepacia.    
   
   
       45 . A composition for inhibiting biofilm formation comprising a compound of  claim 27 . 
   
   
       46 . A composition for inhibiting biofilm formation comprising a compound of  claim 28 . 
   
   
       47 . A composition for inhibiting biofilm formation comprising a compound of  claim 31 . 
   
   
       48 . A compound selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or physiologically acceptable derivative thereof. 
   
   
       49 . A method for inhibiting the production of a virulence factor comprising contact with a compound of  claim 48 . 
   
   
       50 . A composition for inhibiting biofilm formation comprising a compound of  claim 48 .