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 - 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 .