New methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates as selective COX-2 inhibitors and anti-inflammatory agents: Design, synthesis, biological evaluation, and docking study

Abstract

A new method was developed for synthesis of 1,2,4-triazole-3-carboxylates 5a-p and 6 from nitrilimines 3a-p through amination and heterocyclization two-steps reactions. All of 1,2,4-triazole-3-carboxylates 5 and 6 were characterized by spectroscopy technique. Based on the SAR study of anti-inflammation activity, most of these compounds showed potential anti-inflammatory activity on NO inhibition in LPS-induced RAW 264.7 cells (IC₅₀ < 7.0 µM) compared with Celecoxib and Indomethacin. Several potential compounds 5b-h, 5j, 5l, 5n, and 5o were subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. Compound 5d showed extraordinary COX-2 inhibition (IC₅₀ = 17.9 nM) and the best selectivity (COX-1/COX-2 = 1080). Furthermore, 5 mg/kg compound 5d exhibited better in vivo anti-inflammation and gastric protection results compared to 10 mg/kg Indomethacin. Docking experiments of 5d into COX-2 binding pocket have been evaluated. Following the bioactivities experimental data, the potential drug candidate 5d, significantly exhibited better anti-inflammatory effect than Indomethacin.

Keywords: 1,2,4-Triazole; Anti-inflammation; COX-2 inhibitor; Heterocyclization.