Alkynyl and β-ketophosphonates: Selective and potent butyrylcholinesterase inhibitors

Bioorg Chem. 2018 Apr:77:420-428. doi: 10.1016/j.bioorg.2018.01.030. Epub 2018 Feb 20.

Abstract

A series of thirty-three alkynyl and β-ketophosphonates were evaluated for their in vitro acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitory activities using Ellman's spectrophotometric method. None of the examined compounds inhibited AChE activity at tested concentrations while twenty-nine of them showed significant and selective inhibition of BChE with IC50 values between 38.60 µM and 0.04 µM. In addition, structure-activity relationships were discussed. The most effective inhibitors were the dibutyl o-methoxyphenyl alkynylphosphonate 3dc and dibutyl o-methoxyphenyl β-ketophosphonate 4dc. Activities of most potent compounds were also compared with a commercial organophosphorus compound. These results could inspire the design of new inhibitors with stronger activity against BChE.

Keywords: Butyrylcholinesterase; Enzymatic inhibition; Organophosphorus compounds; Phosphonates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alkynes / chemical synthesis
  • Alkynes / chemistry
  • Alkynes / pharmacology*
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Horses
  • Molecular Structure
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Structure-Activity Relationship

Substances

  • Alkynes
  • Cholinesterase Inhibitors
  • Organophosphonates
  • beta-ketophosphonate
  • Acetylcholinesterase
  • Butyrylcholinesterase