Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125–0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents.

具有临床意义的细菌病原体（例如耐甲氧西林的金黄色葡萄球菌（MRSA）和耐万古霉素的金黄色葡萄球菌（VRSA））对抗生素的耐药性正成为对公共卫生的普遍威胁，因此，具有新颖作用机制的新型抗菌剂正在广泛使用。紧急需求。作为开发抗菌剂的持续努力的一部分，我们合理地设计和合成了针对细菌细胞分裂蛋白FtsZ的两个系列的含4,5-二氢异恶唑-5基和4,5-二氢异恶唑-3-基的苯甲酰胺衍生物。 。评价它们对一组革兰氏阳性和阴性病原体的活性表明，化合物A16拥有4,5-二氢异恶唑-5-基的化合物对各种测试菌株（包括耐甲氧西林，耐青霉素和临床分离的金黄色葡萄球菌）表现出出色的抗菌活性（MIC，≤0.125–0.5μg/ mL）。此外，进一步的小鼠感染模型表明，A16可能在体内有效并且对Hela细胞无毒。最后，参考对接结果对结构-活动关系进行了详细的讨论。值得注意的是，用4,5-二氢异恶唑环代替异恶唑环不仅扩大了抗菌谱，而且导致对金黄色葡萄球菌的抗菌活性显着提高。株。综上所述，这些结果表明用于开发新型靶向FtsZ的杀菌剂的有希望的化学型。