文献类型：期刊文献

英文题名：Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer's Disease Agents

作者：Xu, Yixiang[1,2];Zhang, Jian[3];Wang, Huan[3];Mao, Fei[2];Bao, Keting[2];Liu, Wenwen[2];Zhu, Jin[2];Li, Xiaokang[2];Zhang, Haiyan[3,4];Li, Jian[1,2]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China;[4]Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2019

卷号：10

期号：1

起止页码：482

外文期刊名：ACS CHEMICAL NEUROSCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000456351300051)】；

基金：Financial support for this research provided by the National Natural Science Foundation of China (Grants 21702061, 21672064, 81522045), the Shanghai Sailing Program (Grant 17YF1403600), the National Key R&D Program of China (Grant 2017YF130202600), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (Grant 14SG28), the "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDA12040207) and the Fundamental Research Funds for the Central Universities are gratefully acknowledged.

语种：英文

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

摘要：Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer's disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 +/- 0.007 mu M) and MAO-B (IC50 = 2.117 +/- 0.061 mu M), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c center dot HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine induced cognitive impairment in mice. Combined with good oral bioavailability (F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.