Novel organophosphorus–quinolone hybrids as potential antimicrobial agents: design, synthesis, biological evaluation, and in vivo antibacterial effect in bacteria-infected zebrafish model
摘要
A novel series of organophosphorus–quinolone hybrids were designed and synthesized as potential antimicrobial agents through efficient phospho-Mannich reactions. The most potent compound, 5d, demonstrated exceptional activity against methicillin-resistant Staphylococcus aureus (MRSA) with an MIC of 0.5 μg/mL, representing a 16-fold and twofold improvement over norfloxacin and ciprofloxacin, respectively. Structure–activity relationship studies revealed the critical influence of substituent electronic properties and steric bulk, with electron-donating groups enhancing potency. Mechanistic studies indicated that compound 5d not only intercalates into bacterial DNA, but also strongly inhibits DNA gyrase, with a binding energy of − 25.522 kJ/mol. Quantum chemical calculations elucidated the essential role of the organophosphorus moiety as a key hydrogen-bond acceptor. Furthermore, 5d exhibited low cytotoxicity against mammalian cell lines (IC50 > 32 μg/mL across five cell lines), indicating favorable selectivity for bacterial over mammalian cells. Notably, 5d showed minimal propensity to induce bacterial resistance over 16 serial passages (with no significant MIC increase), in contrast to the eightfold MIC increase observed for norfloxacin. Additionally, 5d demonstrated significant in vivo efficacy in a zebrafish MRSA infection model, effectively reducing bacterial load without acute toxicity. These results underscore the potential of 5d as a promising lead compound with potent antibacterial activity, good selectivity, and low resistance development risk.
Graphical abstract