Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification

J Med Chem. 2014 Feb 27;57(4):1378-89. doi: 10.1021/jm401650z. Epub 2014 Feb 7.

Abstract

Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Butyrylcholinesterase / metabolism*
  • Catalysis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Organophosphorus Compounds / metabolism*
  • Oximes / chemistry
  • Oximes / pharmacology*

Substances

  • Imidazoles
  • Organophosphorus Compounds
  • Oximes
  • Butyrylcholinesterase