Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine

Eur J Med Chem. 2014 Jun 23:81:15-21. doi: 10.1016/j.ejmech.2014.05.002. Epub 2014 May 4.

Abstract

Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.

Keywords: Alzheimer's disease; Butyrylcholinesterase inhibitor; Carbamates; Evodiamine; Neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Butyrylcholinesterase / metabolism*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Quinazolines
  • evodiamine
  • Butyrylcholinesterase