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

Abstract

A new series of peptide-like derivatives containing different aromatic amino acids andpossessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para positionof 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 methodusing Wang resin. One of the analogues, i.e., compound 2d, as the representative of these serieswas recognized as the most effective and the highest selective COX-2 inhibitor with IC50 valueof 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 toCOX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside thesecondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquireddisclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine asamino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with highselectivity. Compound 2d can be a good candidate for the development of new hits of COX-2inhibitors.