文献类型：期刊文献

英文题名：Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease

作者：Xu, Yi-xiang[1];Wang, Huan[2,3];Li, Xiao-kang[1];Dong, Sheng-nan[2];Liu, Wen-wen[1];Gong, Qi[2];Wang, Tian-duan-yi[1];Tang, Yun[1];Zhu, Jin[1];Li, Jian[1];Zhang, Hai-yan[2];Mao, Fei[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;[3]Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

年份：2018

卷号：143

起止页码：33

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000428216700004)】；

基金：Financial support for this research was provided by the National Natural Science Foundation of China (Grants 21702061, 21672064, 81522045), Yang-Fan Program from the Science and Technology Commission of Shanghai (Grants 17YF1403600), and the Fundamental Research Funds for the Central Universities.

语种：英文

外文关键词：Multifunctional agents; AChE inhibitors; MAO-B inhibitors; Metal chelating agents; Alzheimer's disease

摘要：A series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-3) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE (vs BuChE, IC50 = 0.324 M, SI > 123) and MAO-B (vs MAO-A, IC50 = 1.427 mu M, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of lb could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu2+-induced A beta(1-42) aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood-brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease. (C) 2017 Elsevier Masson SAS. All rights reserved.