Design, Synthesis and Biological Evaluation of new 1,4-Dihydropyridine (DHP) Derivatives as Selective Cyclooxygenase-2 Inhibitors

Document Type: Research article

Authors

1 Shahid Beheshti Univ. Med. Sci.

2 Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences

3 The Scientific Thechnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.

4 Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University

5 Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran.

Abstract

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.

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