design, synthesis and biological evaluation of 5-oxo-1,4,5,6,7,8 hexahydroquinoline derivatives as selective cyclooxygenase-2 inhibitors

a group of regioisomeric 5-oxo-1,4,5,6,7,8 hexahydroquinoline derivatives possessing a cox-2 so2me pharmacophore at the para position of the c-2 or c-4 phenyl ring, in conjunction with a c-4 or c-2 phenyl (4-h) or substituted-phenyl ring (4-f,4-cl,4-br,4-ome,4-me, 4-no2), were designed for evaluation as selective cyclooxygenase-2 (cox-2) inhibitors. these target 5-oxo-1,4,5,6,7,8 hexahydroquinolines were synthesized via a hansch condensation reaction. in vitro cox-1/cox-2 isozyme inhibition structure-activity studies identified 7,8-dihydro-7,7-dimethyl-2-(4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)quinolin-5(1h,4h,6h)-one (9c) as a potent cox-2 inhibitor (ic50 = 0.17 microm) with a high cox-2 selectivity index (s.i. = 97.6) comparable to the reference drug celecoxib (cox-2 ic50 = 0.05 microm; cox-2 s.i= 405). a molecular modeling study where 9c was docked in active site of cox-2 showed that the p-so2me substituent on the c-2 phenyl ring is inserted into the secondary cox-2 binding site. the structure activity data acquired indicate that the position of the cox-2 so2me pharmacophore and type of substituent are important for cox-2 inhibitory activity.