文献类型：期刊文献

英文题名：Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease

作者：Zhou, Li-Cheng[1];Liang, Ying-Fan[1];Huang, Yi[1];Yang, Gui-Xiang[1];Zheng, Lu-Lu[1];Sun, Jia-Min[1];Li, Yang[1];Zhu, Fu-Li[1];Qian, He-Wen[1];Wang, Rui[1];Ma, Lei[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2021

卷号：219

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000646945500013)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant 81973196), the National Science and Technology Major Project of China (Grant 2018ZX09735002), the 111 Project (Grant BP0719034) and the Natural Science Foundation of Shanghai, China (Grant 19ZR1413900).

语种：英文

外文关键词：Diosgenin; Antioxidant; Anti-beta amyloid; Alzheimer's disease

摘要：The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and A beta (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 +/- 1.9%), 6-OHDA (38.4 +/- 2.4%) and A beta(1-42) (54.4 +/- 2.7%). Molecular docking study suggested the affinity for 5b bound to A beta(1-42) was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to A beta(1-42). The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 A(2)) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Abinjected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. (C) 2021 Elsevier Masson SAS. All rights reserved.