Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China; Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Bioorg Med Chem Lett. 2019 Sep 1;29(17):2448-2451. doi: 10.1016/j.bmcl.2019.07.037. Epub 2019 Jul 23.
To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization.
为了进一步探索我们之前发现的抗真菌先导化合物（1）的构效关系（SARs），设计、合成了一系列联苯咪唑类似物，并评估了它们的体外抗真菌活性。许多合成的化合物对白色念珠菌和热带念珠菌表现出优异的活性。在这些化合物中，2-F 取代类似物 12m 对白色念珠菌、新生隐球菌、烟曲霉和氟康唑耐药白色念珠菌菌株的体外活性最为显著，优于或相当于参考药物氟康唑和伊曲康唑的活性。值得注意的是，化合物 12m 对各种人细胞色素 P450 同工酶的抑制谱较低，对哺乳动物 A549 细胞和 U87 细胞的毒性较低。本研究中建立的 SARs 和结合模式将有助于进一步的先导化合物优化。
