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.
The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Eur J Med Chem. 2017 Sep 8;137:96-107. doi: 10.1016/j.ejmech.2017.05.043. Epub 2017 May 24.
To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
为进一步提高我们之前发现的抗真菌先导化合物（1）的抗曲霉效果，设计、合成了一系列芳香杂环衍生物，并对其进行了体外抗真菌活性评价。许多目标化合物对白色念珠菌和新型隐球菌表现出良好的抑制活性。特别是，异噁唑核更适合提高对曲霉菌属的活性。在这些化合物中，2-F 取代类似物 23g 和 23h 对念珠菌属、新型隐球菌、烟曲霉和氟康唑耐药的白念珠菌菌株表现出最显著的体外活性，其活性优于或可与参考药物氟康唑和伏立康唑相媲美。值得注意的是，化合物 23g 和 23h 对人细胞色素 P450 的各种同工酶表现出低抑制谱和优异的血浆稳定性。
