Background/Objectives: The rise in methicillin-resistant Staphylococcus aureus (MRSA) demands new therapeutic strategies. In this study, a series of 2-(amino)quinazolin-4(3H)-one derivatives were synthesized and evaluated for antistaphylococcal activity. Methods/Results: Through screening against S. aureus ATCC25923 and USA300 JE2, several submicromolar inhibitors were identified. Among them, compound 6l, which contains a 7-chloro substituent on the key parental scaffold, exhibited strong overall antibacterial activity (MIC50: 1.0 µM, ATCC25923; 0.6 µM, JE2) and served as a lead for further structural optimization. Structure–activity relationship analysis showed that substitution at the 2-position was critical, with its optimized analog 6y (3,4-difluorobenzylamine) exhibiting the highest potency (MIC50: 0.36 µM, ATCC25923; 0.02 µM, JE2). Cytotoxicity assays in HepG2 cells revealed six compounds with IC50 values above 20 µM, yielding efficacy windows greater than 10. Compound 6y exhibited an exceptional index (~885). Consistently, in an H460 lung epithelial infection model mimicking MRSA pneumonia, 6y significantly reduced intracellular bacterial loads with minimal host cell damage, outperforming comparator compounds. Conclusions: These findings highlight 2-(amino)quinazolin-4(3H)-one derivatives, particularly 6y, as promising leads for the development of new antistaphylococcal agents.
Lee et al. (Thu,) studied this question.