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

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 = 0.17–28.0 μM range) compared to COX-1 isozyme (IC₅₀ = 21.0 to >100 μM 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 = >100 μM, COX-2: IC₅₀ = 0.17 μM, 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 = 2.85 Å), and one of the oxygen atoms of SO₂NH₂ group forming a hydrogen bond to H90 (SO?N = 2.38 Å).