Design, synthesis and biological evaluation of bambuterol analogues as novel inhibitors of butyrylcholinesterase

Eur J Med Chem. 2017 Jan 27:126:61-71. doi: 10.1016/j.ejmech.2016.08.061. Epub 2016 Aug 26.

Abstract

An increase activity of butyrylcholinesterase is believed to contribute to Alzheimer's disease. Bambuterol is a known potent inhibitor of butyrylcholinesterase, but it has undesired cardiac effects and less lipophilicity. Thirteen bambuterol analogues were synthesized using 1-(3, 5-dihydroxyphenyl) ethanone as a starting material. In-vitro cholinesterase assay established that the majority of the compounds are specific butyrylcholinesterase inhibitors. Out of the 13 compounds, two bambuterol derivatives, BD-6 and BD-11 exhibited similar efficacies in inhibiting butyrylcholinesterase with fewer effects on heart and enhanced possibilities of permeating through the blood-brain barrier as compared to bambuterol. These bambuterol analogues may provide better alternatives for treatments of Alzheimer's disease.

Keywords: Alzheimer's disease; Bambuterol; Butyrylcholinesterase; Specific butyrylcholinesterase inhibitor; YWGBVRAEPOSYRZ-BNMXMQCQSA-N.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Adult
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Chemistry Techniques, Synthetic
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Computer Simulation
  • Drug Design*
  • Heart Rate / drug effects
  • Humans
  • Male
  • Mice
  • Terbutaline / adverse effects
  • Terbutaline / analogs & derivatives*
  • Terbutaline / chemical synthesis
  • Terbutaline / chemistry
  • Terbutaline / pharmacology

Substances

  • Cholinesterase Inhibitors
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Terbutaline
  • bambuterol