设计、合成及苯并杂环类似物作为靶向细胞色素 P45051 抗真菌剂的评价。
Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51.
机构信息
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.
出版信息
Bioorg Med Chem. 2018 Jul 23;26(12):3242-3253. doi: 10.1016/j.bmc.2018.04.054. Epub 2018 Apr 27.
To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
为了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、合成了一系列苯并杂环类似物，并评估了它们的体外抗真菌活性。最有前途的化合物 13s 和 14a 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表现出优异的抗真菌活性，优于或与参考药物氟康唑和伏立康唑相当。GC-MS 分析表明，新型化合物 13s 可能通过抑制真菌羊毛甾醇 14α-脱甲基酶（CYP51），具有与氟康唑类似的作用机制。此外，化合物 13s 和 14a 对各种人细胞色素 P450 同工酶的抑制作用较小，并且具有出色的血浆稳定性。
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