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Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors.

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.
AuthorsLing Wang, Yu Wang, Yiguang Tian, Jinling Shang, Xiaoou Sun, Hongzhuan Chen, Hao Wang, Wen Tan
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 1 Pg. 360-371 (01 01 2017) ISSN: 1464-3391 [Electronic] England
PMID27856236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2016 Elsevier Ltd. All rights reserved.
Chemical References
  • Chalcones
  • Cholinesterase Inhibitors
  • Reactive Oxygen Species
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Rivastigmine
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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