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化学学报
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化学学报 ›› 2010, Vol. 68 ›› Issue (22): 2338-2346. 上一篇    下一篇

研究论文

新型哌嗪并[2,1-a]异喹啉类化合物合成及抗真菌活性的研究

唐辉1,2，郑灿辉1,†，吕加国*,1，付丙月1，周有骏*,1，朱驹1   

  1. (1第二军医大学药学院 上海 200433)
    (2山东大学附属山东省立医院药剂科 济南 250021)
  • 投稿日期:2009-12-11 修回日期:2010-05-21 发布日期:2010-07-25
  • 通讯作者: 周有骏 E-mail:zhouyoujun2006@yahoo.com.cn
  • 基金资助:

    国家自然科学基金项目;863计划

Synthesis and Antifungal Activities in vitro of Novel Pyrazino [2,1-a] Isoquinolin Derivatives

Tang Hui1,2 Zheng Canhui1,† Lü Jiaguo*,1 Fu Bingyue1 Zhou Youjun*,1 Zhu Ju1   

  1. (1School of Pharmacy, Second Military Medical University, Shanghai 200433)
    (2Pharmacy, Provincial Hospital Affiliated to Shandong University, Jinan 250021)
  • Received:2009-12-11 Revised:2010-05-21 Published:2010-07-25

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设计、合成了36个新型哌嗪并[2,1-a]异喹啉类化合物, 并测试了其体外抗真菌活性. 结果表明所有化合物对5种临床致病真菌都有抗真菌活性. 其中化合物5h, 5j～5l, 6g～6k和6l对除白念菌外的4种测试菌的抗真菌活性强于或相当于对照药氟康唑|特别是大多数目标化合物对于氟康唑无效的薰烟曲霉菌显示出较好抗真菌活性. 对接研究显示所设计的目标化合物与靶酶活性腔中氨基酸功能残基结合. 结果表明新型哌嗪并[2,1-a]异喹啉类化合物是一类全新结构类型的抗真菌化合物, 为抗真菌药物研究提供了新的结构类型.

关键词: 抗真菌, 羊毛甾醇14α-去甲基化酶抑制剂, 哌嗪并[2,1-a]异喹啉

A series of novel pyrazino [2,1-a] isoquinolin compounds were designed and synthesized, and their antifungal activities in vitro were evaluated. All these compounds had potent antifungal activity against five pathogenic fungi. Compounds 5h, 5j～5l, 6g～6k, and 6l showed comparable or stronger inhibitory activities against nearly all the test fungi except Candida albicans than that of fluconazole. In particular, the most compounds exhibited activities with broad antifungal spectrum, and showed potent activities against Aspergillus fumigatus, which is not inhibited effectively by fluconazole. Moreover, the mode of action of the pyrazino [2,1-a] isoquinolin molecules showed that the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the residues of apoprotein but without binding with the heme. These pyrazino [2,1-a] isoquinolin provided lead compounds for the development of antifungal drugs. The studies presented here provide a new structural type for the development of novel antifungal agents.

Key words: antifungal, lanosterol 14α-demethylase inhibitor, pyrazino [2,1-a] isoquinolin