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

European Journal of Medicinal Chemistry
Zhipei SangYong Deng

Abstract

A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aβ(1-42) aggregation, Cu(2+)-induced Aβ(1-42) aggregation, human AChE-induced Aβ(1-40) aggregation and disassembled Cu(2+)-induced aggregation of the well-structured Aβ(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study.

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Citations

Oct 22, 2018·Drug Development Research·Zafer SahinŞeref Demirayak
Sep 20, 2017·Future Medicinal Chemistry·Dawid PanekBarbara Malawska
Jul 3, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Derya OsmaniyeGülhan Turan
Nov 11, 2019·International Journal of Molecular Sciences·Hassan RamshiniFabrizio Chiti

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