Modulation of Pathogenicity
The present invention relates to the use of compounds of the general Formula (XIII): In particular the invention refers to a family of compounds that block the quorum sensing system of Gram-negative bacteria, a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of microbial damages and diseases, in particular for diseases where there is an advantage in inhibiting quorum sensing regulated phenotypes of pathogens.
1 . A compound of Formula XIII, or a pharmaceutically acceptable derivative thereof:
wherein
A 7 is independently C═O, C═S, SO 2 , CH—OR 13 , C═NR 12 , or CH 2 —CHOR 13 ;
A 8 is independently C(R 14 ) 2 , O, S, or NR 12 ;
A 9 is independently C═O, C═S, SO 2 , CH—OR 13 , C═NR 12 , or CH 2 —CHOR 13 ;
m is 0, or 1;
q is 0, or 1;
r is 0, or 1;
R 12 is independently H, CH 3 , CH 2 —CH 3 , C 6 H 5 , OCH 3 , OCH 2 —CH 3 , OH, or SH;
R 13 is independently H, CH 3 , or CH 2 —CH 3 ;
R 14 is independently H, alkyl, alkoxy, OH, or SH;
A 5 is a C 3 -C 16 alkyl group optionally substituted by one or more substituents R 3 ; or A 5 is a five-membered heterocyclic group having one N or NR 4 as the ring-constituting atoms other than carbon atoms, and in which the heterocyclic ring may be substituted by one or more substituents R 8 , R 8′ , or R 9 ,
A 6 is a five-membered heterocyclic group having one N or NR 4 as the ring-constituting atoms other than carbon atoms, and in which the heterocyclic ring may be substituted by one or more substituents R 8 , R 8′ , or R 9 ,
R 3 is independently OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO 2 , CN, SO 2 NR 4 R 5 , CONR 4 R 5 , COR 4 , CO 2 R 4 , SO 2 R 4 , SO 3 R 4 , NR 4 R 5 , alkyl, or aryl;
R 4 is H, alkyl, cycloalkyl, aryl or heteroaryl;
R 5 is H, alkyl, aryl or heteroaryl, O-alkyl, O-aryl, or O-heteroaryl; and
R 8 , R 8′ , R 9 is independently H, oxygen, methyl, ethyl, t-butyl, CN, halogen, cycloaryl, haloalkoxy, haloalkyl, amide, alkoxy, NR 4 R 5 , COOR 4 .
2 . The compound according to claim 1 , wherein A 5 is a C 3 -C 16 alkyl group optionally substituted by one or more substituents R 3 .
3 . The compound according to claim 1 , wherein R 4 is alkyl.
4 . The compound according to claim 1 wherein A 6 is one of the groups below:
or wherein m=0 and A 6 is one of the groups below,:
wherein X′, X″, X′″, and X″″ are independently N, NR 4 , CH, or CH 2 ; and
R 8 , R 8′ , and R 9 are independently selected from H, methyl, ethyl, t-butyl, CN, halogen, OH, alkoxy, NR 4 R 5 , COOR 4 .
5 . The compound according to claim 1 wherein m is 1.
6 . The compound according to claim 1 wherein r is 1.
7 . The compound according to claim 6 wherein m is 1.
8 . The compound according to claim 6 wherein A 8 is CH 2 .
9 . The compound according to claim 7 wherein A 7 is C═O.
10 . The compound according to claim 7 wherein A 9 is C═O.
11 . The compound according to claim 10 wherein A 7 is C═O.
12 . The compound according to claim 1 wherein r is 1, m is 0, q is 1, A 7 is C═O, A 9 is C═O, A 8 is CH 2 , A 5 is an optionally substituted C 5 -C 8 alkyl group.
13 . The compound according to claim 1 wherein r is 1, m is 1, q is 1, A 7 is C═O, A 9 is C═O, A 8 is CH 2 , A 5 is an optionally substituted C 5 -C 8 alkyl group and R 12 is CH 3 .
14 . The compound according to claim 21 , selected from the group consisting of compounds 44-62 and 85-86 listed in Table 2.
15 . A pharmaceutical composition comprising a compound according to claim 1 including a pharmaceutically acceptable diluent or carrier.
16 . A method for regulating quorum sensing system of a microorganism comprising contacting the microorganism with a composition comprising a compound according to claim 1 .
17 . The method according to claim 6 , wherein the microorganism is a bacterium.
18 . The method according to claim 16 , wherein the microorganism is a gram negative bacterium.
19 . The method according to claim 16 , wherein quorum sensing of the microorganism is inhibited.
20 . A method for treating or preventing bacterial infection in a patient in need thereof, the method comprising administering to the patient an effective amount of a pharmaceutical composition according to claim 15 .
21 . The method according to claim 20 , wherein the bacterial infection is endocarditis, respiratory and pulmonary infections, bacteremia, central nervous system infections, ear infections including external otitis, eye infections, bone and joint infections, urinary tract infections, gastrointestinal infections and skin and soft tissue infections including wound infections, pyoderma and dermatitis which are caused by Pseudomonas aeruginosa ; pulmonary infections caused by Burkholderia cepacia , gastroenteritis and wound infections caused by Aeromonas hydrophila , sepsis in tropical and subtropical areas caused by Chromobacterium violaceum , diarrhoea with blood and haemolytic uremic syndrome (HUS) caused by Escherichia coli , yersiniosis triggered by Yersinia enterocolitica and Y. pseudotuberculosis , and transfusion-related sepsis and fistulous pyoderma caused by Serratia liquefaciens.
22 . The method according to claim 21 , wherein the pulmonary infection is in an immunocompromized or cystic fibrosis patient.
23 . A method for treating biofilm or inhibiting of the formation of biofilm on an object, wherein the biofilm comprises at least a bacterium having a quorum sensing system, the method comprising regulating the quorum sensing system of the bacterium according to claim 17 .
24 . The method according to claim 23 , wherein the object is medical instrument, a medical device, a preparation of disinfectant, a preparation of cleaning solution, a personal hygiene article, a toiletry, a cosmetic preparation, a ship hull, an industrial system, or an environmental system.
25 . The method according to claim 24 , wherein the industrial system or environmental system is selected from the group consisting of a food processing system, a oil recovery system, a paper manufacturing plant, a water treatment plant, a water distribution system, and a refrigeration system.
26 . The method according to claim 16 , wherein a plant disease is treated or damage to the plants caused by an infection by the microorganism is prevented or alleviated.