Design, Synthesis and Biological Evaluation of 5-Oxo-1,4,5,6,7,8 Hexahydroquinoline Derivatives as Selective Cyclooxygenase-2 Inhibitors

作者：Zarghi Afshin^*; Sabakhi Iman; Topuzyan Vigen; Hajimahdi Zahra; Daraie Bahram

来源：Iranian Journal of Pharmaceutical Research, 2014, 13: 61-69.

• 5-Oxo-1,4,5,6,7,8 hexahydroquinolines
• COX-2 Inhibitors
• Molecular modeling
• Hansch condensation

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-dihydro7,7-dimethyl-2-(4-methoxyphenyl)-4-(4-(methylsulfonyl) phenyl) quinolin-5(1H, 4H, 6H)one (9c) as a potent COX-2 inhibitor (IC50 = 0.17 M) with a high COX-2 selectivity index (S. I. = 97.6) comparable to the reference drug celecoxib (COX-2 IC50 = 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-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.

• 出版日期2014