Novel tacrine-1,2,3-triazole Hybrids: In Vitro, in Vivo Biological Evaluation and Docking Study of Cholinesterase Inhibitors

Eur J Med Chem. 2017 Jan 5;125:1200-1212. doi: 10.1016/j.ejmech.2016.11.008. Epub 2016 Nov 8.

Abstract

A new series of tacrine-1,2,3-triazole hybrids were designed, synthesized, and evaluated as potent dual cholinesterase inhibitors. Most of synthesized compounds showed good in vitro inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 7-chloro-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5l) was found to be the most potent anti-AChE derivative (IC50 = 0.521 μM) and N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5j) demonstrated the best anti-BChE activity (IC50 = 0.055 μM). In vivo studies of compound 5l in Morris water maze task confirmed memory improvement in scopolamine-induced impairment. Also, molecular modeling and kinetic studies showed that compounds 5l and 5j bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CS) of the AChE and BChE.

Keywords: Alzheimer's disease; Cholinesterase; Docking study; Dual binding; Morris water maze; Tacrine-1,2,3-triazole.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterase Inhibitors / therapeutic use
  • Humans
  • Kinetics
  • Male
  • Memory Disorders / drug therapy
  • Memory Disorders / enzymology
  • Molecular Docking Simulation
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / enzymology
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Tacrine / chemistry*
  • Tacrine / pharmacology*
  • Tacrine / therapeutic use
  • Triazoles / chemistry*
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use

Substances

  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Triazoles
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase