Novel tacrine-ebselen hybrids with improved cholinesterase inhibitory, hydrogen peroxide and peroxynitrite scavenging activity

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6737-42. doi: 10.1016/j.bmcl.2013.10.034. Epub 2013 Oct 29.

Abstract

A series of tacrine-ebselen hybrids were synthesised and evaluated as possible multifunctional anti-Alzheimer's disease (AD) agents. Compound 6i, which is tacrine linked with 5,6-dimethoxybenzo[d][1,2]selenazol-3(2H)-one by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitor, with IC50 values of 2.55 and 2.80 nM, respectively. Furthermore, this compound demonstrated similar hydrogen peroxide and peroxynitrite scavenging activity as ebselen by horseradish peroxidase assay and peroxynitrite scavenging activity assay, indicating that this hybrid is a good multifunctional drug candidate for the treatment of AD.

Keywords: Alzheimer’s disease; Antioxidant; Cholinesterase inhibitor; Peroxynitrite scavenging activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / metabolism
  • Animals
  • Azoles / chemistry*
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / metabolism
  • Free Radical Scavengers / pharmacology
  • Horses
  • Humans
  • Hydrogen Peroxide / chemistry*
  • Isoindoles
  • Kinetics
  • Molecular Docking Simulation
  • Organoselenium Compounds / chemistry*
  • Organoselenium Compounds / metabolism
  • Organoselenium Compounds / pharmacology
  • Peroxynitrous Acid / chemistry*
  • Protein Binding
  • Protein Structure, Tertiary
  • Tacrine / analogs & derivatives*
  • Tacrine / chemistry*
  • Tacrine / metabolism
  • Tacrine / pharmacology

Substances

  • 5,6-dimethoxy-2-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)benzo(d)(1,2)selenazol-3(2H)-one
  • Azoles
  • Cholinesterase Inhibitors
  • Free Radical Scavengers
  • Isoindoles
  • Organoselenium Compounds
  • Peroxynitrous Acid
  • ebselen
  • Tacrine
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase