Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors.
A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity (COX-2 IC(50)=0.07 microM; selectivity index=687.1) that was more selective than the reference drug celecoxib (COX-2 IC(50)=0.06 microM; selectivity index=405). A molecular modeling study where 8 was docked in the binding site of COX-2 indicated that the p-MeSO(2) COX-2 pharmacophore group on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg(513), Phe(518) and Val(523)) and the carboxylic acid substituent can interact with Ser(530). The structure activity data acquired indicate that the size and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity.
Ghodsi
Razieh
R
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University MC, Tehran, Iran.
Zarghi
Afshin
A
Daraei
Bahram
B
Hedayati
Mehdi
M
D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012756:Sheep; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D011804:Quinolines; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2