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

作者：Sang, Zhipei; Qiang, Xiaoming; Li, Yan; Xu, Rui; Cao, Zhongcheng; Song, Qing; Wang, Ting; Zhang, Xiaoyu; Liu, Hongyan; Tan, Zhenghuai^*; Deng, Yong^*

来源：European Journal of Medicinal Chemistry, 2017, 135: 307-323.

DOI：10.1016/j.ejmech.2017.04.054

• Alzheimer's disease
• Scutellarein-O-acetamidoalkylbenzylamines
• Multifunctional agents
• Acetylcholinesterase inhibitors
• A beta aggregation inhibitors
• Antioxidant agents

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 A beta(1-42) aggregation, Cu2+-induced A beta(1-42) aggregation, human AChE-induced A beta(1-40) aggregation and disassembled Cu2+-induced aggregation of the well-structured A beta(1-42) 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.

• 出版日期2017-7-28
• 单位四川大学; 南阳师范学院; 四川省中医药科学院