2Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences
3The Scientific Thechnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
4Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University
5Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran.
As a continuous research for discovery of new COX-2 inhibitors, chemical synthesis, in vitro biological activity and molecular docking study of anew group of 1,4-dihydropyridine (DHP) derivatives were presented. Novel synthesized compounds possessing a COX-2 SO2Me pharmacophore at the para position of C-4 phenyl ring, different hydrophobic groups (R1) at C-2 position and alkoxycarbonyl groups (COOR2) at C-3 position of 1,4-dihydropyridine, displayed selective inhibitory activity against COX-2 isozyme. Among them, compound 5e was identified as the most potent and selective COX-2 inhibitor with IC50 value of 0.30 mcgM and COX-2 selectivity index of 92. Molecular docking study was performed to determine probable binding models of compound 5e. The study showed that the p-SO2Me-phenyl fragment of 5e inserted inside secondary COX-2 binding site (Arg513, Phe518, Gly519, and His90). The structure-activity relationships acquired reveal that compound 5e with methyl and ethoxycarbonyl as R1 and COOR2 substitutions has the necessary geometry to provide selective inhibition of the COX-2 isozyme and it can be a good basis for the development of new hits.