Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2016 Apr 15;26(8):2035-9. doi: 10.1016/j.bmcl.2016.02.079. Epub 2016 Feb 27.

Abstract

A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.

Keywords: Alzheimer’s disease; Antioxidant; Aβ aggregation inhibitors; Dual cholinesterase inhibitors; Pterostilbene-O-acetamidoalkylbenzylamines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / metabolism*
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzylamines / chemical synthesis
  • Benzylamines / chemistry
  • Benzylamines / pharmacology*
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Peptide Fragments / metabolism*
  • Protein Aggregates / drug effects*
  • Protein Aggregation, Pathological / drug therapy
  • Stilbenes / chemical synthesis
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Benzylamines
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Protein Aggregates
  • Stilbenes
  • amyloid beta-protein (1-42)
  • Butyrylcholinesterase
  • Cholinesterases