Sulfonamide-Pyrazole derivatives as next-generation Cyclooxygenase-2 enzyme inhibitors: From molecular design to in vivo efficacy.

The current research focuses on the design and synthesis of celecoxib analogues incorporating sulphonamide and pyrazole moieties (4, 5, 6a-e, and 7a-f) with the aim of achieving a broad range of COX-2 selectivity in vitro. Among these, compounds 6b-d, 7a, 7e, and 7d exhibited potent inhibition, with IC values ranging between 0.05 and 0.08 μM, and were selected for in vivo evaluation using the formalin-induced paw edema model. To further assess the safety profile of compound 6d, a histopathological examination of paw tissue was conducted alongside routine blood analyses evaluating key liver and kidney function parameters, including creatinine, urea, AST, and ALT levels. The results indicated normal profiles, comparable to reference drugs celecoxib and indomethacin. Additionally, compound 6d was evaluated for its effect on inflammatory biomarkers using ELISA assays. Markedly, 6d elicited a remarkable reduction in TNF-α (71.43 %) and PGE (77.11 %) levels, surpassing the effects of both celecoxib and indomethacin, confirming its potent anti-inflammatory properties. In terms of analgesic activity, Importantly, cardiac toxicity assessment revealed no adverse effects associated with compound 6d. Finally, compound 6d underwent in silico analysis, including molecular docking and molecular dynamics simulations, which confirmed its selective interaction with the COX-2 active site and favorable free insertion into the selectivity side pocket.