Antioxidant potential of vanillin Schiff base hybrids: Insights from in silico molecular docking, ADMET, and in vitro DPPH assay

Abstract

Oxidative stress is a primary driver of chronic disease. However, many synthetic antioxidants are limited by toxicity and instability. While vanillin is a promising natural scaffold, the influence of electron-withdrawing group (EWG) (i.e. halogen or NO2) on its antioxidant efficacy remains an important area of exploration. This study aimed to synthesise and evaluate vanillin Schiff base hybrids (1a-g) for their antioxidant potential. The synthesised compounds were screened for radical-scavenging activity using DPPH assay. Molecular interactions were explored through docking studies against human 5-lipoxygenase (PDB ID: 6N2W) and further complemented by ADMET profiling to assess pharmacokinetic viability and adherence to Lipinski’s Rule of Five. The derivatives exhibited antioxidant activity, with IC50 values ranging from 386.01 to 1,060.05 µM. Compound 1f emerged as the most active (IC50 = 386.01 µM) among the synthesised compounds. Docking analysis revealed favourable binding affinities (-6.30 to -6.00 kcal/mol) while ADMET analysis showed that vanillin Schiff bases possess a consistent profile of oral drug-likeliness. These findings establish the vanillin Schiff base framework as a potential lead scaffold for further structural refinement. This research contributes to ongoing efforts in antioxidant development in support of the United Nation SDG 3: Good Health and Well-Being.