Marine Natural Product-Derived Tri-iodinated 2-Benzoylquinazolin-4(3 H )-one Alkaloid as a Potent and Selective Agent against MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health. Marine natural products provide a rich source of novel chemical entities for tackling MRSA infections. In this study, a series of halogenated 2-benzoylquinazolin-4(3H)-one derivatives (1−48) was designed and synthesized by innovatively integrating halogen pharmacophores with the biologically validated marine alkaloid penipanoid C. Anti-MRSA assays revealed that the introduction of iodine atoms significantly enhanced the activity of this class of compounds. Compound 48 (CHNQD-01748), bearing three iodine atoms, exhibited the most significant and selective antibacterial effect against the MRSA strain with an MIC value of 4 μg/mL against the reference MRSA strain (ATCC 43300) and 8−16 μg/mL against three clinical isolates. Further investigations revealed that 48 possessed a sustained antibacterial effect, potent biofilm-disrupting and biofilm-inhibitory activity, a long half-life, and a favorable preliminary safety profile in the models tested. An in vivo antibacterial assay demonstrated that 48 had vancomycin-comparable efficacy against localized MRSA skin infections yet provided superior suppression of systemic dissemination, inhibiting bacterial loads by >95% in the spleen, lung, and kidney. These findings showed the promising potential of 48 as a potent agent for the treatment of MRSA infections.