Vanillin-Derived Multifunctional Agents: Structure-Based Design, Docking, and In Vitro Evaluation of Antitubercular, Anti-Inflammatory, and Antioxidant Activities

Abstract

Tuberculosis remains a major global health burden, highlighting the urgent need for new therapeutic agents with improved efficacy and safety. In this study, a series of vanillin-derived biphenyl ether analogues inspired by the nimesulide scaffold was designed and synthesized as multifunctional candidates targeting tuberculosis-associated pathologies. The compounds were prepared via Schiff base formation followed by microwave-assisted Ullmann coupling and were structurally confirmed by FTIR, NMR, and mass spectrometry. In silico evaluation revealed favorable physicochemical and ADME profiles, supporting drug-likeness. Molecular docking against enoyl-acyl carrier protein reductase (InhA, PDB ID: 1P44) demonstrated strong binding affinities, with analogue 3e exhibiting the most favorable docking score (−8.8 kcal/mol). In vitro antitubercular assays showed that compound 3e maintained activity across the full concentration range tested (0.8–100 µg/mL), while compounds 3a and 3c remained active at concentrations where isoniazid was ineffective and compounds 4b and 4d displayed comparable potency to the reference drug. Anti-inflammatory and antioxidant evaluations further identified compounds with pronounced activity, notably compounds 4a, 3b, 4b, and 4d. Overall, these findings indicate that vanillin-based biphenyl ethers—particularly compound 3e—represent promising multifunctional scaffolds for further optimization and preclinical development as next-generation antitubercular agents.