文献类型：期刊文献

英文题名：Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents

作者：Li, Xiaokang[1];Wang, Huan[2];Lu, Zhengyu[1];Zheng, Xinyu[1];Ni, Wei[1];Zhu, Jin[1];Fu, Yan;Lian, Fulin[2,3];Zhang, Naixia[3];Li, Jian[1];Zhang, Haiyan[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]Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China

年份：2016

卷号：59

期号：18

起止页码：8326

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000384035300011)】；

基金：Financial support of this research provided by the Fundamental Research Funds for the Central Universities (Grant 22A201514054), the Chinese Postdoctoral Science Foundation (Grant 2015M580300), and the National Natural Science Foundation of China (Grant 8152200403) is gratefully acknowledged.

语种：英文

摘要：Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, Sr, IC50 = 0.204 mu M, SI > 196; St, IC50 = 0.067 mu M, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced A beta aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound Sr displayed appropriate blood brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of, scopolamine-induced amnesia mice. The multifunctional profiles of Sr and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.