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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Authors | Ling Wang, Yu Wang, Yiguang Tian, Jinling Shang, Xiaoou Sun, Hongzhuan Chen, Hao Wang, Wen Tan |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 25
Issue 1
Pg. 360-371
(01 01 2017)
ISSN: 1464-3391 [Electronic] England |
PMID | 27856236
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2016 Elsevier Ltd. All rights reserved. |
Chemical References |
- Chalcones
- Cholinesterase Inhibitors
- Reactive Oxygen Species
- Acetylcholinesterase
- Butyrylcholinesterase
- Rivastigmine
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Topics |
- Acetylcholinesterase
(metabolism)
- Alzheimer Disease
(drug therapy)
- Butyrylcholinesterase
(metabolism)
- Catalytic Domain
- Cell Line, Tumor
- Chalcones
(chemical synthesis, pharmacology, toxicity)
- Cholinesterase Inhibitors
(chemical synthesis, pharmacology, toxicity)
- Humans
- Hydrogen Bonding
- Kinetics
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- Oxidative Stress
(drug effects)
- Reactive Oxygen Species
(metabolism)
- Rivastigmine
(analogs & derivatives, chemical synthesis, pharmacology, toxicity)
- Structure-Activity Relationship
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