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

ABSTRACT

A group of regioisomeric 5-oxo-1,4,5,6,7,8 hexahydroquinoline derivatives possessing a COX-2 SO[2]Me 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-NO[2]], 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 [IC[50] = 0.17 M] with a high COX-2 selectivity index [S.I. = 97.6] comparable to the reference drug celecoxib [COX-2 IC[50] = 0.05 mM; COX-2 S.I= 405]. A molecular modeling study where 9c was docked in active site of COX-2 showed that the p-SO[2]Me 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 SO[2]Me pharmacophore and type of substituent are important for COX-2 inhibitory activity