New tilomisole-based benzimidazothiazole derivatives as anti-inflammatory agents: Synthesis, in vivo, in vitro evaluation, and in silico studies

New tilomisole-based benzimidazothiazole derivatives were designed and synthesized in this work. Their anti-inflammatory activity was assessed through the in vivo carrageenan rat paw edema model, and the in vitro COX inhibition assay. Compounds 13, 20, 30, 40, 43, and 46 demonstrated values of inhibition of induced edema in the in vivo assay comparable to celecoxib. All the synthesized compounds expressed their activity on COX-2 Enzyme more than COX-1, proving their advantageous selectivity. In addition, compounds 13, 16, 20, 25, and 46 displayed lower IC₅₀ values than celecoxib as a reference drug against COX-2 enzyme; having values of 0.09, 13.87, 32.28, 33.01, and 5.18 nM respectively vs 40.00 nM for celecoxib. Particularly, the most active compound (13) with its extreme potency (400 folds more potent than celecoxib) exhibited a notable high selectivity index (SI = 159.5). In silico studies, including ADMET prediction, compliance to Lipinski's rule of five, and molecular docking into the active site of both COX isozymes were conducted for the synthesized compounds. The results suggested that these compounds are good candidates for orally active drugs, and docking revealed higher number of interactions with COX-2 for 13 as the most active compound compared with COX-1 reflecting its advantageous selectivity and explaining its extreme potency.