肉桂酰三氮唑化合物的设计、合成及抗阿尔茨海默症活性评价  

Design,synthesis and anti-Alzheimer's disease activity evaluation of cinnamyl triazole compounds

作　　者：雷文聚 蔡中頔 谭林杰 刘蜜敏 曾利 孙婷 易红[1] 刘睿 李卓荣[1] LEI Wen-ju;CAI Zhong-di;TAN Lin-jie;LIU Mi-min;ZENG Li;SUN Ting;YI Hong;LIU Rui;LI Zhuo-rong(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所,北京100050

出　　处：《药学学报》2025年第1期150-163,共14页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82073709)。

摘　　要：本研究设计、合成19个肉桂酰胺/酯三氮唑类化合物,并对其抗阿尔茨海默症(Alzheimer's disease,AD)活性进行评价。在APPswe细胞模型实验中,化合物4f具有良好的抗Aβ介导的神经细胞毒性(EC50=2.03±2.45μmol·L^(-1))和由此引起的ACh E活性的异常升高(IC50=4.88±4.70μmol·L^(-1));进一步研究发现,化合物4f(1、5和25 mg·kg^(-1))可有效改善β-淀粉样蛋白1-42(β-amyloid protein 1-42,Aβ_(1-42))损伤小鼠的空间认知和学习记忆障碍,通过促进非淀粉样蛋白、抑制淀粉样蛋白途径和Tau蛋白磷酸化改善Aβ_(1-42)诱导的神经退行性病变(实验中所有操作均获得中国医学科学院医药生物技术研究所伦理委员会批准,批准号:IMB-20220908D701)。化合物4f作为治疗AD的一个有前途的先导物,本研究为其后续研发提供了理论依据。19 cinnamamide/ester-triazole compounds were designed,synthesized and evaluated for their anti-Alzheimer's disease(AD)activity.Among them,compound 4f displayed excellent anti-β_(1-42)amyloid protein(Aβ)-mediated cytotoxicity(ECso=2.03±2.45μmol·L^(-1))in APPswe cells and acetylcholinesterase inhibiton(ICso=4.88±4.70μmol·L^(-1)).Further study indicated that,at dosages of(1,5 and 25 mgkg^(-1)),compound 4f was effective in improving spatial learning and memory deficits in Aβ_(1-42)impaired mice,which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway,along with the suppression of Aβ_(1-42)induced Tau phosphorylation.All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology(IMB-20220908D701).In conclusion,compound 4f holds promise as a lead candidate for AD treatment,and the present study lays the foundation for its subsequent development.

关 键 词：肉桂酰胺/酯-三氮唑 设计合成 乙酰胆碱酯酶 Β-淀粉样蛋白 阿尔茨海默症 

分 类 号：R914[医药卫生—药物化学]