Rational design and biological evaluation of naturally inspired indole-oxadiazole derivatives as potent COX inhibitors.

Indole-oxazole and indole-oxadiazole scaffolds, inspired by natural products, provide versatile platforms for the development of selective COX inhibitors. In this study, a novel series of indol-oxadiazole derivatives was rationally designed by incorporating N-alkyl-substituted indole moieties at the 5-position and optimizing aryl substitutions at the 2-position of the oxadiazole core. The synthesized compounds were systematically evaluated for COX-1 and COX-2 inhibition in vitro, revealing potent and selective activity. The compounds exhibited potent in vitro COX inhibition, with IO-2 showing balanced dual activity against COX-1 (IC50 = 0.198 ± 0.022 µM) and COX-2 (IC50 = 0.158 ± 0.028 µM), and IO-13 displaying strong COX-1 inhibition (IC50 = 0.175 ± 0.063 µM). Celecoxib served as the reference COX-2 inhibitor (IC50 = 0.119 ± 0.055 µM). Molecular docking and dynamics simulations provided insights into binding interactions and the stability of the COX complex within the COX active site. Selected derivatives were well tolerated in healthy cell lines, indicating favorable safety profiles. Structure-activity relationship analysis highlighted the critical role of the indole nucleus and strategic oxadiazole substitutions in modulating COX inhibitory potency and selectivity. These findings establish indole-oxadiazoles as a promising scaffold for selective COX inhibition and a foundation for future rational drug design.