Benzyl-Modified Quinolone-Aminopyrimidine Hybrids with Potent Anti-MRSA Activity and a High Barrier to Resistance.

A series of novel quinolone-aminopyrimidine hybrids were designed and synthesized through benzyl-position modification. Among them, A3 and A5 exhibited promising anti-MRSA activity, low cytotoxicity, and a low propensity for resistance development. Notably, A5 showed favorable metabolic stability in both HLMs and RLMs, whereas A3 displayed excessively prolonged half-lives, suggesting a potential risk of in vivo accumulation. Overall, A5 was identified as a promising lead compound for further antibacterial development.