Acta Chimica Sinica ›› 2007, Vol. 65 ›› Issue (1): 37-42. Previous Articles     Next Articles

Original Articles

基于真菌14α-去甲基化酶的非氮唑类抗真菌先导化合物的设计、合成及其体外抗真菌活性研究

朱驹, 吕加国, 周有骏*, 李耀武, 陈军, 郑灿辉   

  1. (第二军医大学药学院药物化学教研室 上海 200433)
  • 收稿日期:2006-05-11 修回日期:2006-09-12 出版日期:2007-01-14 发布日期:2007-01-14
  • 通讯作者: 周有骏

Design, Synthesis and in vitro Antifungal Activities of Non-azole Lead Compound Based on Lanosterol 14α-Demethylase of Fungi

ZHU Jü; LÜ Jia-Guo; ZHOU You-Jun*; LI Yao-Wu; CHEN Jun; ZHENG Can-Hui   

  1. (Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433)
  • Received:2006-05-11 Revised:2006-09-12 Online:2007-01-14 Published:2007-01-14
  • Contact: ZHOU You-Jun

Non-azole lead molecules were designed by coupling structure-based de novo design based on the structure of lanosterol 14α-demethylase (CYP51). The chemical synthesis and the evaluation of in vitro antifungal activities of them were reported. The results exhibited that all of the lead compounds showed potent antifungal activities., especially compounds 5f and 5g, which had stronger or equal antifungal activities against 5 test fungi than that of fluconazole. The studies presented here provided the antifungal lead compounds. Because the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the apoprotein, which was different from the azole antifungal agents. The studies presented here afford the opportunity to develop novel antifungal agents that specifically interact with the residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.

Key words: lanosterol 14α-demethylase of fungi, inhibitor, design, synthesis, antifungal activity