Microwave-assisted synthesis and dual in silico–in vitro profiling of vanillin azo-Schiff base hybrids for antimicrobial potential

Abstract Researchers have demonstrated substantial interest in bioactive compounds derived from natural resources, such as vanillin, owing to their significant potential in drug development. Here, we report the efficient synthesis of hybrid azo-Schiff bases derived from vanillin 2(a–h) using vanillin azo 1(a–h) as natural product-based precursors, achieved via microwave irradiation to yield significant amounts (67–83%, 6 min) compared to conventional heating (38–53%, 36 h). Compounds 2(a–h) exhibited enhanced antibacterial activity against S. aureus (inhibition zones of 9–11 mm) compared to 1(a–h) (7–9 mm) and the parent vanillin, which showed no inhibition. Similarly, 2(a–h) demonstrated superior activity against E. coli (8–11 mm) relative to 1(a–h) (7–9 mm) and vanillin (no inhibition). Compound 2b exhibited the most potent antibacterial activity among the synthesised compounds, with inhibition zones of 11.03 ± 0.12 mm against E . coli and 11.20 ± 0.10 mm against S. aureus , comparable to the standard antibiotic ampicillin (11–12 mm). Compound 2b also revealed a strong binding affinity of − 7.3 kcal/mol in molecular docking analysis, alongside an energy gap of 3.45 eV as determined by DFT calculations using Gaussian 09, indicating favourable electronic properties for antimicrobial activity. The ADMET studies supported natural product-based hybrids derived from vanillin as suitable drug candidates. This research significantly advances drug design by presenting potent in vitro antibacterial agents derived from natural products, characterised by promising pharmacological and physicochemical properties. Graphical Abstract