Department of Molecular Genetics, University of Groningen, Groningen, Netherlands.
Bioland Laboratory (Guangzhou Regenerative Medicine and Health - Guangdong Laboratory),Guangzhou, 510530, PR China.
Eur J Med Chem. 2022 Sep 5;239:114553. doi: 10.1016/j.ejmech.2022.114553. Epub 2022 Jun 21.
The rapid emergence of antibiotic resistance has become a prevalent threat to public health, thereby development of new antibacterial agents having novel mechanisms of action is in an urgent need. Targeting at the cytoskeletal cell division protein filamenting temperature-sensitive mutant Z (FtsZ) has been validated as an effective and promising approach for antibacterial drug discovery. In this study, a series of novel biphenyl-benzamides as FtsZ inhibitors has been rationally designed, synthesized and evaluated for their antibacterial activities against various Gram-positive bacteria strains. In particular, the most promising compound 30 exhibited excellent antibacterial activities, especially against four different Bacillus subtilis strains, with an MIC range of 0.008 μg/mL to 0.063 μg/mL. Moreover, compound 30 also showed good pharmaceutical properties with low cytotoxicity (CC > 20 μg/mL), excellent human metabolic stability (T = 111.98 min), moderate pharmacokinetics (T = 2.26 h, F = 61.2%) and in vivo efficacy, which can be identified as a promising FtsZ inhibitor worthy of further profiling.
抗生素耐药性的迅速出现已成为公共卫生的普遍威胁，因此急需开发具有新型作用机制的新型抗菌剂。针对细胞骨架细胞分裂蛋白丝状温度敏感突变体 Z（FtsZ）的靶向已被验证为一种有效的有前途的抗菌药物发现方法。在这项研究中，设计、合成了一系列新型联苯-苯甲酰胺类 FtsZ 抑制剂，并评估了它们对各种革兰氏阳性菌菌株的抗菌活性。特别是最有前途的化合物 30 表现出优异的抗菌活性，特别是对四种不同的枯草芽孢杆菌菌株，其 MIC 范围为 0.008μg/mL 至 0.063μg/mL。此外，化合物 30 还具有良好的药物特性，其细胞毒性低（CC>20μg/mL），人代谢稳定性好（T=111.98min），药代动力学中等（T=2.26h，F=61.2%），体内疗效好，可被鉴定为一种有前途的 FtsZ 抑制剂，值得进一步研究。
