Design, synthesis and evaluation of scutellarein- O -acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease

• DOI: 10.1016/j.ejmech.2017.04.054
• Publication Date: 2017-04-22T22:30:18Z
• Authors: Zhipei Sang; Xiaoming Qiang; Yan Li; Rui Xu; Zhongcheng Cao; Qing Song; Ting Wang; Xiaoyu Zhang; Hongyan Liu; Zhenghuai Tan; Yong Deng
• Keywords: Models, Molecular; 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Scopolamine; Mice, Inbred Strains; Flavones; PC12 Cells; Rats; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Alzheimer Disease; Cell Line, Tumor; Drug Design; Animals; Cholinesterases; Humans; Cholinesterase Inhibitors; Maze Learning

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.