Vanillin-derived Chalcone–schiff Base Hybrids: Synthesis, ADMET Profiling, Molecular Docking, and Antimicrobial Evaluation

Abstract

The emergence of antimicrobial resistance has increased the need for novel bioactive molecules with improved efficacy and sustainable synthetic approaches. This study aimed to develop vanillin-derived chalcone–Schiff base hybrids using a green chemistry-assisted synthetic strategy and to evaluate their antimicrobial potential through experimental and computational studies. A base-catalysed synthetic route was employed under mild conditions using ethanol as a green solvent and vanillin as a renewable starting material. The synthesized hybrids (10a–10h) were characterized by FTIR and ¹H NMR spectroscopy. Drug-likeness and physicochemical properties were assessed using in silico ADME analysis. Antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, and Candida albicans was evaluated using the Kirby–Bauer disc diffusion method. Molecular docking studies were performed against DNA gyrase (PDB ID: 2XCT) and lanosterol 14α-demethylase (PDB ID: 5TZ1). Eight chalcone–Schiff base hybrids were synthesized in moderate to good yields (54–72%). Among the tested compounds, 10c exhibited the highest antibacterial activity, while 10d showed the strongest antifungal activity, producing inhibition zones of 17–21 mm comparable to the reference drugs ciprofloxacin and fluconazole. Molecular docking demonstrated favourable binding affinities toward both target enzymes, and ADME predictions indicated compliance with Lipinski's rule of five with a low predicted toxicity risk. The study demonstrates that integrating green chemistry principles with molecular hybridization can generate biologically active compounds while reducing the environmental impact of synthesis. The findings support the potential of vanillin-derived chalcone–Schiff base hybrids as promising antimicrobial leads. A limitation of the study is the absence of in vivo validation and comprehensive pharmacokinetic evaluation. Green chemistry-assisted synthesis provided an efficient and sustainable route to biologically active chalcone–Schiff base hybrids. The combined antimicrobial, molecular docking, and ADME results identify compounds 10c and 10d as promising candidates for further optimization and development as antimicrobial agents.