1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, biological evaluation and molecular modeling studies

Abstract

A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO2NH2 attached to one aryl ring and various substituents (H, F, Cl, CH3 or OCH3) attached to the other aryl ring. The effects of size and flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by increasing the size of an alkyl linker chain [(–CH2)n, where n=0, 1, 2]. In vitro COX-1/COX-2 inhibition studies showed that all compounds (14–18, 21–25 and 28–32) are more potent inhibitors of COX-2 isozyme (IC50=0.17–28.0μM range) compared to COX-1 isozyme (IC50=21.0 to >100μM range). Within the group of 1,4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and selectivity (COX-1: IC50=>100μM, COX-2: IC50=0.17μM, SI >588). Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data. Results of molecular docking studies revealed that COX-2 pharmacophore SO2NH2 in compound 30 is positioned in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO2NH2 group being hydrogen bonded to Q192 (N⋯OC=2.85Å), and one of the oxygen atoms of SO2NH2 group forming a hydrogen bond to H90 (SO⋯N=2.38Å).