Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase

Bioorg Med Chem. 2014 Jun 15;22(12):3213-9. doi: 10.1016/j.bmc.2014.03.045. Epub 2014 Apr 13.

Abstract

Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 μM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 μM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 μM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Polyamine conjugates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Amyloid beta-Peptides
  • Anthracenes / chemistry
  • Anthracenes / pharmacology*
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Catalytic Domain
  • Cell Proliferation / drug effects*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Drug Design
  • Hep G2 Cells
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Polyamines / chemistry
  • Polyamines / pharmacology*
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • 2-(4-aminobutylamino)-N-(anthracen-9-yl)acetamide hydrochloride
  • 2-(6-aminohexylamino)-N-(anthracen-9-yl)acetamide hydrochloride
  • Acetamides
  • Amyloid beta-Peptides
  • Anthracenes
  • Cholinesterase Inhibitors
  • Polyamines
  • Butyrylcholinesterase
  • anthracene