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

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

基于真菌羊毛甾醇14α-去甲基化酶(CYP51)活性位点的三维结构设计并合成了新型四氢异喹啉类抗真菌先导化合物.体外抗真菌活性研究显示:设计的先导化合物具有较好的抗真菌活性.其中化合物5f和5g对于5种测试菌的抗真菌活性强于或相当于对照药物氟康唑.先导分子通过与靶酶活性腔氨基酸残基的非共价键结合产生抗真菌作用,避免与血红素辅基Fe原子发生配位结合,为一类具有新作用机理的非氮唑类抗真菌先导化合物.本研究为抗真菌药物研究提供了新的结合方式及结构类型.

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.