Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 94, Issue -, Pages 348-366Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.02.063
Keywords
Alzheimer's disease; Scutellarein-O-alkylamines; Multifunctional agents; Acetylcholinesterase inhibitors; Metal-chelating agents; A beta aggregation inhibitors
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Funding
- Chinese National Natural Science Foundation [20872099]
- Research Fund for the Doctoral Program of Higher Education [20110181110079]
- Sichuan Academic and Technical Leader Training Foundation [2012DTPY003]
- National Science and Technology Major Project on Key New Drug Creation and Manufacturing Program [2013ZX093013 04-002]
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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 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. 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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