协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究  

Design,synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans

作　　者：赵晶[1,2] 李冉[2] 代黎[2] 蔡瞻[2] 张大志[1,2] 姜远英[3] 

机构地区：[1]福建中医药大学药学院,福建福州350122 [2]第二军医大学药学院有机化学教研室,上海200433 [3]第二军医大学药学院新药研究中心,上海200433

出　　处：《药学实践杂志》2016年第2期129-134,共6页Journal of Pharmaceutical Practice

基　　金：国家自然科学基金(21272270)

摘　　要：目的基于前期研究的胡椒乙胺和咖啡酸类化合物分别具有协同氟康唑（FCZ）抗耐药真菌的作用,将两类化合物结构片段通过适当的连接子连接,设计合成新型化合物,研究其体外抗耐药真菌活性。方法以胡椒乙胺为起始原料,与叔丁氧羰基保护的氨基酸缩合,随后脱保护基,再与咖啡酸缩合,形成目标化合物。对4个中间体和9个目标化合物进行体外协同FCZ抗耐药白念珠菌作用评价。结果9个目标化合物均具有协同FCZ（8.0μg/ml）抗耐药白念珠菌活性,MIC80为0.5~2.0μg/ml;其中,3b、3f、3g、3i等化合物的MIC80均为0.5μg/ml,与对照化合物7b和5相当。结论将胡椒乙胺和咖啡酸通过4-哌啶甲酸（3b）、缬氨酸（3g）、亮氨酸（3f）、异亮氨酸（3i）连接,可以获得协同FCZ抗耐药真菌的高活性化合物。Objective 3,4-Methylenedioxyphenethylamine and caffeic acid derivatives have been proven previously in our group to produce activity against drug resistant fungi synergistic with fluconazole（FCZ）.The two pharmacophores were coupled by amino acids as linkers in this project in order to design and synthesize the novel compounds and investigate the activity against drug resistant fungi in vitro.Methods 3,4-Methylenedioxyphenethylamine initially reacted with Boc-protected amino acids,following deprotection and coupling reaction with caffeic acid,to get nine title compounds.All title compounds as well as four intermediates were subjected to antifungal activity screening for fluconazole resistant Candida albicans in vitro.ResultsNine title compounds showed synergistic antifungal activity for drug resistant Candida albicans with fluconazole at a concentration range of 0.5-2.0μg/ml.Among them,compounds 3b,3f,3g and 3ishowed the higher activity with the same MIC80 value of 0.5μg/ml,which is comparable to those of the control compounds 7band 5.Conclusion Linking 3,4-methylenedioxyphenethylamine and caffeic acid with piperidine-4-carboxylic acid（3b）,valine（3g）,leucine（3f）and isoleucine（3i）led to novel compounds with high synergistic antifungal activity against drug resistant Candida albicans combined with fluconazole.

关 键 词：抗真菌 耐药 协同 合成 白念珠菌 

分 类 号：R915[医药卫生—微生物与生化药学]