Design, synthesis and dual anticancer and antibacterial evaluation of novel 1,3,4-oxadiazole-2-thiol derivatives targeting EGFR and DNA Gyrase B: integrated docking, DFT and ADMET studies

Novel 1,3,4-oxadiazole-2-thiol derivatives (8a–j) were synthesized via multistep reactions and characterized using IR, 1H NMR, and 13C NMR spectroscopy. The compounds were evaluated for dual anticancer and antibacterial activities through computational and experimental approaches. Molecular docking against EGFR (1M17) and DNA gyrase B (2XCT) revealed compound 8h as the most potent EGFR inhibitor (−7.528 kcal/mol), surpassing methotrexate (−7.448 kcal/mol), while compound 8c demonstrated superior DNA gyrase B binding (−7.263 kcal/mol), exceeding ciprofloxacin (−6.11 kcal/mol) by 19%. In vitro cytotoxicity against A549 human lung carcinoma cells identified compound 8c as the most active anticancer agent (IC50 = 14.59 ± 0.19 µg/mL), comparable to methotrexate (IC50 = 11.82 ± 1.22 µg/mL). Antibacterial screening against S. aureus, E. coli, and K. pneumoniae revealed compound 8d as the most effective broad-spectrum agent (MIC = 25 µg/mL across all strains), demonstrating 2-fold superior activity against S. aureus versus ciprofloxacin. Comprehensive DFT calculations on compound 8c elucidated frontier orbital energies (HOMO-LUMO gap: 4.7528 eV), global reactivity descriptors, optimized geometry, Mulliken charge distribution, and topological properties (MEP, RDG, ELF, LOL). ADMET profiling revealed favorable drug-likeness with 0–1 Lipinski violations, optimal lipophilicity (cLogP: 2.7–3.97), and good predicted oral absorption (57–64%). These findings establish 1,3,4-oxadiazole-2-thiol derivatives as promising dual-action therapeutic scaffolds.