Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents

Eur J Med Chem. 2016 Oct 21:122:17-26. doi: 10.1016/j.ejmech.2016.06.022. Epub 2016 Jun 15.

Abstract

A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.

Keywords: Anti-Alzheimer agent; Antioxidation; Aβ aggregation; Cholinesterase; Flavonoid.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / chemistry
  • Animals
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Cell Death / drug effects
  • Chemistry Techniques, Synthetic
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterase Inhibitors / therapeutic use
  • Dimethylamines / chemistry*
  • Drug Design*
  • Flavonoids / chemical synthesis*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Flavonoids / therapeutic use
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Kinetics
  • Molecular Docking Simulation
  • PC12 Cells
  • Peptide Fragments / chemistry
  • Protein Aggregates / drug effects
  • Protein Conformation
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Dimethylamines
  • Flavonoids
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase