文献类型：期刊文献

英文题名：Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

作者：Li, Xiaokang[1];Lu, Jian[2];Xu, Yixiang[1];Wang, Jiaying[2];Qiu, Xiaoxia[1];Fan, Lei[3];Li, Baoli[1];Liu, Wenwen[1];Mao, Fei[1];Zhu, Jin[1];Shen, Xu[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Nanjing Univ Chinese Med, Sch Med & Life Sci, Nanjing 210023, Peoples R China;[3]Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2020

卷号：10

期号：4

起止页码：646

外文期刊名：ACTA PHARMACEUTICA SINICA B

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000526087100006)】；

基金：Financial support for this research 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), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_1600, China) are gratefully acknowledged.

语种：英文

外文关键词：Alzheimer's disease; Autophagy; Nitazoxanide; beta-amyloid; Tau protein

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 promoting beta-amyloid (A beta) 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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.