新型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 Antifungal Evaluation of Novel Compounds as Synergists of Fluconazole against Drug-resistant Candida Albicans

作　　者：郝雨濛 蔡瞻[2] 倪廷峻弘[2] 谢斐[2] 张大志[1,2] 姜远英[2] HAO Yu-meng;CAI Zhan;NI Ting-jun-hong;XIE Fei;ZHANG Da-zhi;JIANG Yuan-ying(School of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350112,China;School of Pharmacy,the Second Military Medical University,Shanghai 200433,China)

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,上海200433

出　　处：《解放军药学学报》2018年第6期477-483,共7页Pharmaceutical Journal of Chinese People's Liberation Army

基　　金：国家自然科学基金资助;No.81673280;81830106

摘　　要：目的基于前期开展的协同氟康唑抗耐药白念珠菌的小分子化合物构效关系研究,设计合成新型化合物并进行体外抗耐药真菌活性筛选。方法以3,4-(亚甲二氧基)肉桂酸及各类胺或腈为起始原料,经Pd/C还原、LiAlH4还原、烃基化取代、酰胺化及Suzuki偶联等反应得到两大类共计26个目标化合物,评价其与氟康唑合用对耐药白念珠菌的作用效果。结果目标化合物在与氟康唑(8.0μg·ml^(-1))联用时,均具有协同作用,化合物1n优于对照化合物3e。结论获得了活性化合物和清晰的构效关系。Objective To design,synthesize and evaluate novel compounds in order to restore thein vitroantifungal activity of fluconazole against drug-resistant Candida albicans based on our previous studies of structural optimization and structure-activity relationships on a series of small molecules as synergists of fluconazole.Methods Amidation reaction of 3,4-(methylenedioxy)cinnamic acid was initiated with various amines,followed by Suzuki coupling reaction before a total of 26 target compounds in two major categories were obtained.Their synergistic antifungal activity with fluconazole was evaluatedinvitroagainst two fluconazole-resistant Candida albicans isolates.Results All the target compounds exhibited synergistic antifungal activity with fluconazole(8.0μg·ml^-1)against the two drug-resistant isolates.Compound 1 nshowed higher activity than the control compound 3 e.Conclusion Novel synergists with high potent activity against drug-resistant fungi have been obtained,and clear structure-activity relationships are identified.

关 键 词：协同作用 抗真菌 耐药 白念珠菌 合成 

分 类 号：R914.5[医药卫生—药物化学]