期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 9, 页码 2636-2641出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.02.095
关键词
Flavonoid derivatives; Acetylcholinesterase inhibitors; Anti-beta-amyloid aggregation; Biometal-chelating agents; Molecular modeling
资金
- Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT-IRT1193]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Cultivation Fund of the Key Scientific and Technical Innovation Project, Ministry of Education of China [707033]
A new series of flavonoid derivatives were designed, synthesized and evaluated as potential multifunctional AChE inhibitors against Alzheimer's disease. Most of them exhibited potent AChE inhibitory activity, high selectivity for AChE over BuChE, and moderate to good inhibitory potency toward A beta aggregation. Specifically, compound 12c was the strongest AChE inhibitor, being 20-fold more potent than galanthamine and twofold more potent than tacrine, and it also had ability to inhibit A beta aggregation (close to the reference compound) and to function as a metal chelator. Molecular modeling and enzyme kinetic study revealed that it targeted both the catalytic active site and the peripheral anionic site of AChE. Consequently, this class of compounds deserved to be thoroughly and systematically studied for the treatment of Alzheimer's disease. (C) 2013 Elsevier Ltd. All rights reserved.
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