Modulation of Pathogenicity
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 . A compound of Formula (I)
or a pharmaceutically acceptable salt or physiologically functional derivative thereof, wherein
A 1 is pyridinyl or pyrimidinyl, each of which may be optionally substituted with one or more R 3 ;
p is 0;
Y 1 is —C(O)— or —C(S)—;
R 1 is H or alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more R 3 ;
n is 0 or 1;
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 alkyl, aryl, or heteroaryl, each optionally substituted with one or more R 3 ;
each R 3 independently is OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloallyl, 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.
2 . The compound of claim 1 wherein n is 0.
3 . The compound of claim 2 wherein A 2 is phenyl, thienyl, pyrrolyl, or pyridinyl, each optionally substituted with one or more R 3 .
4 . The compound of claim 3 wherein each A 2 is substituted with one or more of C 1-6 alkyl, CO 2 (C 1-6 alkyl), C 1-6 haloalkyl, O(C 1-6 haloalkyl), O(C 14 , alkyl), or halogen.
5 . The compound of claim 1 wherein n is 1.
6 . The compound of claim 5 wherein A 2 is C 1-12 alkyl.
7 . The compound of claim 1 wherein A 1 is
wherein each a independently is 0, 1, or 2.
8 . The compound of claim 1 wherein Y 1 is C(O).
9 . The compound of claim 1 wherein Y 2 is C(O).
10 . The compound of claim 1 wherein R 1 is H.
11 . The compound of claim 1 wherein R 2 is H.
12 . A compound selected from:
or a pharmaceutically acceptable salt or physiologically acceptable derivative thereof.
13 . A method for inhibiting the production of a virulence factor comprising contact with a compound of claim 1 .
14 . A method for inhibiting the production of a virulence factor comprising contact with a compound of claim 12 .
15 . The method of claim 13 for the treatment or prevention of bacterial damage or disease.
16 . The method of claim 14 for the treatment or prevention of bacterial damage or disease.
17 . The method of claim 15 wherein the bacteria is Pseudomonas aeruginosa or Burkholderia cepacia.
18 . The method of claim 16 wherein the bacteria is Pseudomonas aeruginosa or Burkholderia cepacia.
19 . A composition for inhibiting biofilm formation comprising a compound of claim 1 .
20 . A composition for inhibiting biofilm formation comprising a compound of claim 12 .