Design, synthesis and evaluation of a novel metal chelator as multifunctional agents for the treatment of Alzheimer's disease

Bioorg Chem. 2019 Jun:87:720-727. doi: 10.1016/j.bioorg.2019.03.064. Epub 2019 Mar 28.

Abstract

A series of compounds following the lead compounds including deferasirox and tacrine were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most synthesized compounds exhibited good multifunctional activities in inhibiting acetylcholinesterase (bAChE), and chelating metal ions. Especially, compound TDe demonstrated significant metal chelating property, a moderate acetylcholinesterase (AChE) inhibitory activity and an antioxidant activity. Results from the molecular modeling indicated that TD compounds were mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of TcAChE. Moreover, TDe showed a low cytotoxicity but a good protective activity against the injury caused by H2O2. These results suggest that TD compounds might be considered as attractive multi-target cholinesterase inhibitor and will play important roles in the treatment of AD.

Keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Deferasirox; Metal chelator; Multifunctional agents; Tacrine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Biphenyl Compounds / antagonists & inhibitors
  • Cattle
  • Cell Survival / drug effects
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Free Radical Scavengers / chemical synthesis
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology*
  • Hydrogen Peroxide / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Picrates / antagonists & inhibitors
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Biphenyl Compounds
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Coordination Complexes
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Picrates
  • Hydrogen Peroxide
  • 1,1-diphenyl-2-picrylhydrazyl
  • Acetylcholinesterase