Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors

Document Type: Research article


1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.


A new series of peptide-like derivatives containing different aromatic amino acids and
possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position
of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2)
inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method
using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series
was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value
of 0.08 μM and COX-2 selectivity index of 351.2, among the other synthesized compounds.
Molecular docking study was operated to determine possible binding models of compound 2d to
COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the
secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired
disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as
amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high
selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2


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