Green synthesis of pyridine-benzofuran hybrids with anti-inflammatory activity alongside in silico study.

A series of anti-inflammatory pyridine-benzofuran hybrid derivatives were synthesized from 2-acetylbenzofuran and natural aldehydes via a mild and efficient multicomponent reaction. Structures were confirmed using infrared (IR) and NMR spectroscopy. Anti-inflammatory effects were evaluated in the carrageenan-induced paw edema model in adult male rats. Among all tested compounds, 7a and 7e demonstrated the most potent dose-dependent inhibition, reaching 61.2% and 60.3% at 200 mg/kg (∗∗p < 0.001), respectively, compared with indomethacin (78.5% at 10 mg/kg). Molecular docking studies against the COX-2 receptor identified compounds 7a, 7b, and 7f as having the most favorable binding energies (below -8 kcal/mol). Integrating in vivo and in silico findings, compounds 7a and 7f emerged as top candidates. Compound 7a was selected for a 100-ns molecular dynamics simulation, which confirmed the stability of the ligand-protein complex and sustained effective interactions with the enzyme, establishing 7a as a promising anti-inflammatory lead candidate.