Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis

Bioorg Chem. 2015 Aug:61:7-12. doi: 10.1016/j.bioorg.2015.05.005. Epub 2015 May 21.

Abstract

This article describes discovery of a novel and new class of cholinesterase inhibitors as potential therapeutics for Alzheimer's disease. A series of novel isoalloxazine derivatives were synthesized and biologically evaluated for their potential inhibitory outcome for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds exhibited high activity against both the enzymes AChE as well as BuChE. Of the synthesized compounds, the most potent isoalloxazine derivatives (7m and 7q) showed IC50 values of 4.72 μM and 5.22 μM respectively against AChE; and, 6.98 μM and 5.29 μM respectively against BuChE. These two compounds were further evaluated for their anti-aggregatory activity for β-amyloid (Aβ) in presence and absence of AChE by performing Thioflavin-T (ThT) assay and Congo red (CR) binding assay. In order to evaluate cytotoxic profile of these two potential compounds, cell viability assay of SH-SY5Y human neuroblastoma cells was performed. Further, to understand the binding behavior of these two compounds with AChE and BuChE enzymes, docking studies have been reported.

Keywords: Alzheimer’s disease; Cholinesterase’s inhibition; Cytotoxicity; Isoalloxazine; β-Amyloid.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / pathology
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / therapeutic use
  • Cholinesterase Inhibitors / toxicity
  • Drug Evaluation, Preclinical
  • Flavins / chemistry*
  • Flavins / therapeutic use
  • Flavins / toxicity
  • Humans
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Flavins
  • isoalloxazine
  • Acetylcholinesterase
  • Butyrylcholinesterase