伊曲康唑类衍生物的合成及体外抗真菌活性  

Synthesis and in vitro Antifungal Activity of Itraconazole Derivatives

作　　者：马光群 张胜男 梁伦海 柴晓云 赵风兰[1] 孟庆国[1] MA Guang-qun;ZHANG Sheng-nan;LIANG Lun-hai;CHAI Xiao-yun;ZHAO Feng-lan;MENG Qing-guo(School of Pharmacy,Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China;School of Pharmacy,Naval Medical University,Shanghai,200433,China)

机构地区：[1]烟台大学药学院,分子药理和药物评价教育部重点实验室(烟台大学),新型制剂与生物技术药物研究山东省高校协同创新中心,山东烟台264005 [2]海军军医大学药学院,上海200433

出　　处：《烟台大学学报（自然科学与工程版）》2022年第4期390-397,共8页Journal of Yantai University(Natural Science and Engineering Edition)

基　　金：国家自然科学基金资助项目(21602250);烟台市科技创新发展计划资助项目(2020XDRH105)。

摘　　要：通过亲核取代反应、水解、叠氮反应和缩合反应设计合成一系列伊曲康唑类衍生物。经^(1)H NMR和MS确证,所合成的目标化合物顺-N-{[2-(2,4-二氯苯基)-2-(^(1)H-1,2,4-三唑-1-基)-甲基-1,3-二氧戊环-4-基]甲基}-[4-(2-取代氨基乙氧基)]苯甲酰胺(A1—A13),均为新化合物。采用微量液基稀释法来检测目标化合物的体外抗真菌活性,结果表明:所合成的13个化合物对大部分所试菌株具有抑制活性,特别是对白念珠菌(Candida albicans);化合物A1、A2、A6抗真菌活性较好,对白念珠菌的抑制活性是伊曲康唑活性的250倍,是氟康唑的32倍以上;此外,化合物A6对近平滑假丝酵母菌的抑制活性与伊曲康唑相当。因此,侧链引入苯甲酰胺结构能够有效增强氮唑类衍生物的体外抗真菌的活性。A series of itraconazole derivatives are designed and synthesized by nucleophilic substitution reaction, hydrolysis, azide reaction and condensation reaction. The target compounds cis-N-{[2-(2 Magne4-dichlorophenyl)-2-(^(1)HMur1 pyryl)-(4-triazole-1-yl)-methyl-1 minute 3-dioxolane-4-yl] methyl}-[4-(2-substituted aminoethoxy)] benzamides(A1-A13) are confirmed by ^(1)H NMR and MS. Micro liquid dilution method is used to detect the antifungal activity of the target compound in vitro. The results show that the 13 compounds synthesized have inhibitory activities against most of the tested strains, especially Candida albicans. Compounds A1, A2 and A6 have good antifungal activity. The inhibitory activity against Candida albicans is more than 250 times than that of itraconazole and more than 32 times than that of fluconazole. In addition, the inhibitory activity of compound A6 against Candida parapsilosis is equivalent to that of itraconazole. Therefore, the introduction of benzamide structure into the side chain can effectively enhance the antifungal activity of azole derivatives in vitro.

关 键 词：氮唑类衍生物 伊曲康唑类衍生物 合成 体外抗真菌活性 

分 类 号：R914.5[医药卫生—药物化学]