Design,synthesis, biological evaluation,and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors |
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Authors: | Ling Wang Yu Wang Yiguang Tian Jinling Shang Xiaoou Sun Hongzhuan Chen Hao Wang Wen Tan |
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Affiliation: | 1. Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China;2. Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China |
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Abstract: | 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. |
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Keywords: | Cholinesterase inhibition Chalcone-rivastigmine hybrids Alzheimer’s disease Antioxidative Molecular docking |
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