新型三唑类化合物的合成及抗真菌活性  

Synthesis and antifungal activity of novel triazole antifungal agents

作　　者：盛春泉[1] 朱杰[1] 张万年[1] 宋云龙[1] 张珉[1] 季海涛[1] 余建鑫[1] 姚建忠[1] 杨松[1] 缪震元[1] 

机构地区：[1]第二军医大学药学院药物化学教研室,上海200433

出　　处：《药学学报》2004年第12期984-989,共6页Acta Pharmaceutica Sinica

基　　金：国家"863"项目(2002AA233091);军队"十五"指令性课题(01l057);国家自然科学基金重点项目(30430750)

摘　　要：目的　寻找广谱、高效、低毒的新一代三唑类抗真菌药物。方法　根据靶酶活性位点的空间特征、各种力 场和关键残基分布,设计并合成了21个1 (1,2,4 三唑 1H 1 基) 2 (2,4 二氟苯基) 3 (4 取代 1 哌嗪基) 2 丙醇类 化合物,并测定了体外抑菌活性。结果　体外抑菌测试结果表明,所有化合物对8种致病真菌均有一定程度的抗真 菌活性,对深部真菌的活性明显优于浅部真菌。在哌嗪的各种取代基中,苯基和杂环取代的抗真菌活性明显优于苯 甲酰基取代。结论　有多个化合物的体外抗真菌活性明显高于氟康唑和特比萘芬,其中化合物VIII 1,4,5和IX 3 具有广谱、高活性的优点,值得进一步研究。Aim A series of triazole antifungal agents were synthesized to search for novel triazole antifungal agents with more potent activity,less toxicity and broader spectrum. Methods Twenty-one 1-(1H-1,2,4-triazolyl)-2-(2,4-diflurophenyl)-3-(4-substituted-1-piperazinyl)-2-propanols were synthesized,on the basis of the three dimensional structure of P450 cytochrome 14 α -sterol demethylase(CYP51) and their antifungal activities were also evaluated. Results Results of preliminary biological tests showed that most of title compounds exhibited activity against the eight common pathogenic fungi to some extent and the activities against deep fungi were higher than that against shallow fungi. In general,phenyl and pyridinyl analogues showed higher antifungal activity than that of the phenylacyl analogues. Conclusion Several title compounds showed higher antifungal activities than fluconazole and terbinafine. Compound VIII-1,4,5 and IX-3 showed the best antifungal activity with broad antifungal spectrum and were chosen for further study.

关 键 词：三唑类 合成 抗真菌活性 构效关系 

分 类 号：R914.5[医药卫生—药物化学]