苯腙类果糖-1,6-二磷酸醛缩酶新型抑制剂的合成及其抗真菌活性研究(英文)  

Synthesis and antifungal activities of phenylhydrazono derivatives as the novel fructose-1,6-bisphosphate aldolase inhibitors

作　　者：郭丽 郭彦荣 任彦亮[3] 韩新亚 GUO Li;GUO Yanrong;REN Yanliang;HAN Xinya(Hubei Ecological and Environmental Monitoring Center Station,Wuhan 430072,China;School of Chemistry and Chemical Engineering,Anhui University of Technology,Maanshan,Anhui 243002,China;Laboratory of Pesticide&Chemical Biology,Key Laboratary of Ministry of Education,College of Chemistry,Central China Normal University,Wuhan 430079,China)

机构地区：[1]湖北省生态环境监测中心站,武汉430072 [2]安徽工业大学化学与化工学院,安徽马鞍山243002 [3]华中师范大学化学学院,农药与化学生物学教育部重点实验室,武汉430079

出　　处：《华中师范大学学报（自然科学版）》2020年第3期405-412,418,共9页Journal of Central China Normal University：Natural Sciences

基　　金：国家重点研发计划政府间国际科技创新合作重点专项项目(2017YFE0118200);国家自然科学基金项目(21202056);安徽省重点研究与开发计划项目(201904b11020025);安徽省自然基金面上项目(1908085MB35);安徽省高等学校自然科学研究项目(重点项目)(KJ2018A0040);山东大学微生物技术国家重点实验室开放课题(M2017-11)。

摘　　要：白色念珠菌果糖-1,6-二磷酸醛缩酶(CaFBA-Ⅱ)被认为是开发新型抗真菌药物的一个潜在新靶标.本课题组前期的研究中报道了β-酰腙-α,γ-二羰基化合物对CaFBA-Ⅱ具有一定的抑制活性.在本研究中,几类苯腙类化合物被发现可以高效抑制CaFBA-Ⅱ.实验结果显示,R2位上引入NO2有利于提高化合物的酶体活性,尤其是同时在R3位置引入磺酸基后,化合物2g的CaFBA-Ⅱ抑制活性达到了亚纳摩尔级别(IC50=200nmol·L-1).以化合物2g为代表,运用分子动力学模拟(MD)和DOX方法,对化合物2g与CaFBA-Ⅱ的结合模式也进行了系统研究.值得注意的是,本研究中设计的大多数苯腙类化合物都对白色念珠菌具有一定的抗真菌活性(MIC80=16~64μg·mL-1).因而表明以苯腙类化合物为药物先导结构进行优化改造是设计开发新型抗真菌药物的一条可行途径.Fructose-1,6-bisphosphate aldolase fromC.albicans(CaFBA-Ⅱ)is an attractive new target for the discovery of drugs to combat invasive fungal infection.Our previous study demonstrated thatβ-arylhydrazono-α,γ-dicarbonylderivatives exhibit moderate inhibitory against CaFBA-Ⅱ.Herein,several new phenylhydrazono derivatives were found to potently inhibit CaFBA-Ⅱ.The experimental results show that the NO2 group in the R2 position is favorable,but COOH,SO3 H and halogen atom are unfavorable for their CaFBA-Ⅱ inhibitory activities.Especially,when the R3 was substituted by sulfonic acid group,compound 2 g possessed the highest inhibitory activity(IC50=200 nmol·L-1).Furthermore,compound 2 g were selected as representative molecule,the binding mode of 2 g and the surrounding residues in the active site of CaFBA-Ⅱ were elucidated by jointly using DOX methods and molecular dynamics(MD)simulations.Notably,antifungal experiments demonstrate that most of our designed compounds possess moderate inhibitory activities(MIC80 =16-64μg· mL-1)against C.albicans.The present results suggest that the phenylhydrazono derivatives can be used as the lead compounds of novel drugs against fungal pathogens of humans in the future.

关 键 词：新型抑制剂 合理药物设计 苯腙类衍生物 白色念珠菌醛缩酶 抗真菌活性 

分 类 号：O625.6[理学—有机化学]