Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer's disease agents

Bioorg Med Chem Lett. 2017 Jan 15;27(2):232-236. doi: 10.1016/j.bmcl.2016.11.067. Epub 2016 Nov 24.

Abstract

The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Keywords: Alzheimer’s disease; Amyloid beta; Antioxidant; Cholinesterase inhibition; β-Carbolines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / analysis*
  • Amyloid beta-Peptides / biosynthesis
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Carbolines / chemical synthesis
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Carbolines
  • Cholinesterase Inhibitors
  • Cholinesterases