Sabakhi Iman, Topuzyan Vigen, Hajimahdi Zahra, Daraei Bahram, Arefi Hadi, Zarghi Afshin
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran. ; The Scientific Thechnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
The Scientific Thechnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
Iran J Pharm Res. 2015 Fall;14(4):1087-93.
As a continuous research for discovery of new COX-2 inhibitors, chemical synthesis, in vitro biological activity and molecular docking study of a new 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 μM 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 (Arg(513), Phe(518), Gly(519), and His(90)). 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.
作为对新型COX-2抑制剂发现的持续研究，本文介绍了一组新型1,4-二氢吡啶（DHP）衍生物的化学合成、体外生物活性及分子对接研究。新合成的化合物在1,4-二氢吡啶的C-4苯环对位具有COX-2 SO2Me药效团，在C-2位具有不同的疏水基团（R1），在C-3位具有烷氧羰基（COOR2），对COX-2同工酶表现出选择性抑制活性。其中，化合物5e被鉴定为最有效和选择性的COX-2抑制剂，IC50值为0.30 μM，COX-2选择性指数为92。进行分子对接研究以确定化合物5e可能的结合模式。研究表明，5e的对-SO2Me-苯基片段插入到COX-2二级结合位点（Arg(513)、Phe(518)、Gly(519)和His(90)）内。所获得的构效关系表明，以甲基和乙氧羰基作为R1和COOR2取代基的化合物5e具有提供对COX-2同工酶选择性抑制的必要几何结构，并且它可以成为开发新活性化合物的良好基础。
