DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL VANILLIN-BASED CHALCONE-ACETAMIDE HYBRIDS CONTAINING ELECTRON-WITHDRAWING, ELECTRON DONATING, AND HALOGENATED ARYL MOIETIES AS POTENT ANTI-INFLAMMATORY AGENTS

Abstract

A series of thirty novel vanillin-chalcone-acetamide derivatives were synthesized and characterized to develop potent anti inflammatory agents. All compounds were evaluated for COX-1/COX-2 inhibition, BSA denaturation, and nitric oxide suppression in LPS-stimulated RAW 264.7 cells. Compound 1a (4-nitro derivative) exhibited the most promising activity with excellent COX-2 inhibition (IC₅₀ = 1.45 µM, SI = 33.52), significant BSA protection (78.4%), and strong NO inhibition (68.7% at 25 µM). Six lead compounds were further assessed in in vivo models. In the carrageenan-induced paw edema model, 1a (20 mg/kg) showed 71.2% inhibition, superior to indomethacin (68.2%) and parent vanillin (25.8%). In the cotton pellet granuloma model, 1a achieved 57.1% inhibition and significantly reduced TNF-α, IL-6, and PGE₂ levels. Acute toxicity studies confirmed good safety up to 2000 mg/kg. The findings highlight 1a as a promising lead for the development of safer anti-inflammatory agents.