New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

Bioorg Chem. 2016 Aug:67:1-8. doi: 10.1016/j.bioorg.2016.05.004. Epub 2016 May 14.

Abstract

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5μM for EeAChE and 153.8μM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4μM (EeAChE) and 277.8μM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Azepines
  • Cholinesterase Inhibitors
  • Isoquinolines
  • Cholinesterases