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 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.
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Afshin
A
Zarghi
The Scientific Thecnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
Iman
I
Sabakhi
The Scientific Thecnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
Vigen
V
Topuzyan
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Zahra
Z
Hajimahdi
Department of Toxicology, School of Medicine, Tarbiat Modarres University of Medical Sciences, Tehran, Iran.
Bahram
B
Daraie
4; 5; 5-Oxo-1; 6; 7; 8 hexahydroquinolines; COX-2 Inhibitors; Hansch condensation; Molecular modeling