Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer’s disease  

作　　者：Xiaokang Li Jian Lu Yixiang Xu Jiaying Wang Xiaoxia Qiu Lei Fan Baoli Li Wenwen Liu Fei Mao Jin Zhu Xu Shen Jian Li 

机构地区：[1]State Key Laboratory of Bioreactor Engineering,Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China [2]School of Medicine and Life Sciences,Nanjing University of Chinese Medicine,Nanjing 210023,China [3]Center for Drug Safety Evaluation and Research,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

出　　处：《Acta Pharmaceutica Sinica B》2020年第4期646-666,共21页药学学报（英文版）

基　　金：provided by the National Sciences and Technology Major Project of China,(2018ZX09711002-003-010);the National Natural Science Foundation of China,(81872747,21672064);the 111 Project(B07023,China);the Chinese Postdoctoral Science Foundation(2018M641946);the Shanghai Sailing Program(19YF1412600,China);the Shanghai Morning Light Program(18CG33,China);the National Special Fund for State Key Laboratory of Bioreactor Engineering(2060204,China);Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX18_1600,China).

摘　　要：Drug repurposing is an efficient strategy for new drug discovery.Our latest study found that nitazoxanide(NTZ),an approved anti-parasite drug,was an autophagy activator and could alleviate the symptom of Alzheimer’s disease(AD).In order to further improve the efficacy and discover new chemical entities,a series of NTZ-based derivatives were designed,synthesized,and evaluated as autophagy activator against AD.All compounds were screened by the inhibition of phosphorylation of p70S6K,which was the direct substrate of mammalian target of rapamycin(mTOR)and its phosphorylation level could reflect the mTOR-dependent autophagy level.Among these analogs,compound 22 exhibited excellent potency in promotingβ-amyloid(Aβ)clearance,inhibiting tau phosphorylation,as well as stimulating autophagy both in vitro and in vivo.What’s more,22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice.These results demonstrated that 22 was a potential candidate for the treatment of AD.

关 键 词：Alzheimer’s disease AUTOPHAGY NITAZOXANIDE Β-AMYLOID Tau protein 

分 类 号：R971[医药卫生—药品]