Structure-guided design and synthesis of Etoricoxib analogues for selective COX-2 inhibition: in vitro assessment and computational insights with prospective in vivo confirmation.

The selective inhibition of cyclooxygenase-2 (COX-2) is an effective approach for managing inflammatory disorders; however, safety concerns related to current coxibs highlight the need for better alternatives. This study presents the rational design, synthesis, and evaluation of a series of novel etoricoxib-inspired pyridine-based derivatives as potential selective COX-2 inhibitors. Systematic exploration of structure-guided modifications, including heterocyclic scaffold hybridization, pyridine attachment position, and aryl substitution, was conducted to clarify structure-activity relationships. In vitro enzymatic assays demonstrated that multiple compounds displayed significant COX-2 inhibition with advantageous selectivity indices over COX-1, notably compounds 8e, 8g, and 18b, which exhibited potency comparable to celecoxib. The most promising candidates underwent further in vivo evaluation utilizing the carrageenan-induced paw edema model, exhibiting significant anti-edematous activity. Compound 8g demonstrated the most significant and enduring reduction in paw swelling and tissue weight, surpassing the efficacy of reference drugs. Mechanistic investigations demonstrated significant downregulation of NF-κB and its downstream inflammatory mediators, such as COX-2, iNOS, TNF-α, and IL-1β. The lead compounds demonstrated notable analgesic activity in the hot plate test, with no observable hepatic, renal, or cardiac toxicity. Molecular docking and molecular dynamics simulations demonstrated stable binding in the COX-2 active site, and in silico ADME analysis suggested favorable drug-likeness. These findings collectively identify compound 8g as a promising multi-target anti-inflammatory candidate for further development.