Introduction

Inflammatory disorders remain a major therapeutic challenge, with current treatments (NSAIDs, corticosteroids) often limited by safety concerns. The inflammatory cascade is largely driven by cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Dual inhibition of COX-2 and 5-LOX has emerged as a promising strategy to achieve effective anti-inflammatory activity with reduced side effects. Acetamide derivatives are known to exhibit diverse medicinal effects.

The present study is based on the synthesis and evaluation of 4-aminoacetanilide scaffolds towards COX-2 and 5-LOX inhibition.

Method

The inhibitory activity of eight synthesized 4-aminoacetanilide derivatives was assessed against COX-2 and LOX using fluorometric and spectrophotometric assays, respectively. IC₅₀ values were determined and compared with the reference drugs Aspirin (COX-2) and Baicalein (LOX). Additionally, molecular docking studies were performed to elucidate the binding interactions of the most active compounds within the catalytic sites of COX-2 and LOX

Results
AI-06 showed notable potency against COX-2 (IC₅₀: 31.2 µM), while AI-02, AI-03, and AI-06 demonstrated strong inhibition of LOX with IC₅₀ values of 14.1, 19.2, and 26.5 µM, respectively. Structure–activity relationship (SAR) analysis indicated that both the position and nature of substituents played a critical role in determining inhibitory activity. Molecular docking further revealed key binding interactions responsible for the observed potency.

Conclusion
The findings suggest that AI-02, AI-03, AI-06, and AI-08 hold promise as dual COX-2/5-LOX inhibitors and could be further optimized as potential anti-inflammatory agents.