新型吡喃并[2,3-b]萘醌类乙酰胆碱酯酶抑制剂的设计合成及生物活性研究  

Design,Synthesis and Biological Evaluation of Pyrano[2,3-b]-naphthoquinone Derivatives as Acetylcholinesterase Inhibitors

作　　者：杜川黔 谢宝花 贺明 胡志烨 刘豫 何雪 刘凡玉 程晨 周海兵 黄胜堂 董春娥 Du Chuanqian;Xie Baohua;He Ming;Hu Zhiye;Liu Yu;He Xue;Liu Fanyu;Cheng Chen;Zhou Hai-Bing;Huang Shengtang;Dong Chun'e(Hubei Province Engineering and Technology Research Centre for Fluorinated Pharmaceuticals,School of Pharmaceutical Sciences,Wuhan University,Wuhan 430071;Laboratory of Cardiovascular,Cerebrovascular and Metabolic Disorder,Hubei University of Science and Technology,Xianning,Hubei 437100;College of Life Sciences,Wuhan University,Wuhan 430072)

机构地区：[1]武汉大学药学院湖北省有机氟类药物工程技术研究中心,武汉430071 [2]湖北科技学院药学院心脑血管代谢紊乱实验室,湖北咸宁437100 [3]武汉大学生命科学学院,武汉430072

出　　处：《有机化学》2020年第7期2035-2044,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.81773557);湖北省重大专项(No.2018ACA123);湖北科技学院糖尿病重点实验室开放基金(No.2020-21XZ002)资助项目.

摘　　要：设计、合成了一系列新型吡喃并[2,3-b]萘醌类衍生物.抗胆碱抑制活性测试显示,与丁酰胆碱酯酶(BuChE)相比,大部分化合物显示出对乙酰胆碱酯酶(AChE)的高选择性和良好的抑制活性.其中活性最好的化合物(2-氨基-4-(3-氰基苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]亚甲基-3-甲腈)(3n),其AChE抑制活性IC50值为1.22μmol/L,比BuChE高164倍.此外,分子对接模拟研究为理解这些化合物的作用机制、效力及选择性提供了理论支持.这些新型有效且高度选择性的AChE抑制剂的发现为开发阿尔茨海默症的潜在治疗药物提供了先导化合物.A novel synthetic methodology was developed and a series of pyrano[2,3-b]naphthoquinone derivatives were designed and synthesized in excellent yields.Most of these compounds showed effective anti-AChE activities and high selectivity for acetylcholinesterase(AChE)over butyrylcholinesterase(BuChE).Among them,(2-Amino-4-(3-cyanophenyl)-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile)(3n)was significantly potent,with an IC50 value of 1.22µmol/L for AChE,which was 164-fold higher than butyrylcholinesterase(BuChE)in vitro.Moreover,molecular modeling provides valuable information for understanding the potency and selectivity of this kind of compounds for AChE.Consequently,these potent and highly selective AChE inhibitors are potential leads for development of the drug for treatment of Alzheimer’s disease.

关 键 词：吡喃并[2 3-b]萘醌 乙酰胆碱酯酶抑制剂 阿尔兹海默症 分子模拟 

分 类 号：TQ464.8[化学工程—制药化工]