Synthesis and biological evaluation of novel β-keto ether-triazole hybrids as dual antimicrobial and anticancer agents

The growing need for multifunctional agents to overcome antibiotic resistance and infection-related complications in immunocompromised cancer patients necessitates the development of dual-action therapeutics. Herein, a series of β-keto ether–triazole hybrids incorporating a 5-methyl-1-(4-nitrophenyl)-1 H-1,2,3-triazole moiety were synthesized via a one-step protocol and characterized by IR, NMR, and single-crystal X-ray diffraction. Crystallographic and Hirshfeld surface analyses revealed well-defined geometries stabilized by C–H···O and O–H···O interactions. DFT calculations showed excellent agreement with experimental structures (RMSD < 0.04 Å) and HOMO–LUMO energy gaps of 3.04–3.50 eV. MEP analysis indicated localized electrophilic regions in compound 3 and greater charge delocalization in compound 9. Biologically, compound 3 displayed potent antibiofilm activity, achieving 97% inhibition of methicillin-resistant Staphylococcus aureus, while compound 9 showed moderate yet selective cytotoxicity toward hepatocellular carcinoma cells (HepG2) (IC₅₀ = 63.28 µg/mL) with low toxicity to normal Wi38 cells. ADME profiling correlated solubility with antimicrobial activity and lipophilicity with cytotoxic effects, revealing that the high solubility of compound 3 favours antibacterial activity, while the greater lipophilicity and metabolic stability of compound 9 support its anticancer profile. These findings highlight β-keto ether–triazole hybrids as promising scaffolds for dual antimicrobial and anticancer applications.