期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 1, 页码 360-371出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.11.002
关键词
Cholinesterase inhibition; Chalcone-rivastigmine hybrids; Alzheimer's disease; Antioxidative; Molecular docking
资金
- Science and Technology Planning Project of Guangdong Province [2015B010109004]
- Natural Science Foundation of Guangdong Province [2016A030310421]
- National Natural Science Foundation of China [81502984, 81373395, 81573415]
- Fundamental Research Funds for the Central Universities [2015ZM049]
- China Postdoctoral Science Foundation [2015M572325]
- Shanghai Municipal Science and Technology Commission [14431905600]
- Guangdong Provincial Key Laboratory of Construction Foundation [2011A060901014]
- Guangdong Key Laboratory of Fermentation and Enzyme Engineering, SCUT [FJ2015006]
A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro-and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment. (C) 2016 Elsevier Ltd. All rights reserved.
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