title: Design, Synthesis and Biological Evaluation of New 1, 4-Dihydropyridine (DHP) Derivatives as Selective Cyclooxygenase-2 Inhibitors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Iman
authors.initials: I
authors.lastname: Sabakhi
authors.affiliation: The Scientific Thechnological Centre of Organic and Pharmaceutical Chemistry NASRAAL. Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia.
authors.forename: Vigen
authors.initials: V
authors.lastname: Topuzyan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Hajimahdi
authors.affiliation: Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Bahram
authors.initials: B
authors.lastname: Daraei
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran.
authors.forename: Hadi
authors.initials: H
authors.lastname: Arefi
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical sciences, Tehran, Iran.
authors.forename: Afshin
authors.initials: A
authors.lastname: Zarghi
keywords: 1; 4-Dihydropyridine (DHP) Derivatives; COX-2 Inhibitors; Molecular modeling; Synthesis