Novel deoxyvasicinone and tetrahydro-beta-carboline hybrids as inhibitors of acetylcholinesterase and amyloid beta aggregation

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127659. doi: 10.1016/j.bmcl.2020.127659. Epub 2020 Oct 31.

Abstract

A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetylcholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer's disease. The results revealed that the derivatives had multifunctional profiles, including AChE inhibition, Aβ1-42 aggregation inhibition, and neuroprotective properties. Inspiringly, hybrids 8b and 8d displayed excellent inhibitory activities against hAChE (IC50 = 0.93 and 1.08 nM, respectively) and Aβ1-42 self-aggregation (IC50 = 19.71 and 2.05 μM, respectively). In addition, 8b and 8d showed low cytotoxicity and good neuroprotective activity against Aβ1-42-induced damage in SH-SY5Y cells.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Deoxyvasicinone; Tetrahydro-β-carboline; β-Amyloid peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alkaloids / chemistry
  • Alkaloids / pharmacology*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism*
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cell Line
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism*
  • Protein Aggregates / drug effects*
  • Protein Aggregation, Pathological / drug therapy
  • Protein Aggregation, Pathological / metabolism

Substances

  • Alkaloids
  • Amyloid beta-Peptides
  • Carbolines
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • norharman
  • Acetylcholinesterase
  • vasicinone