Design of a potent reactivator of tabun-inhibited acetylcholinesterase--synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203)

J Med Chem. 2007 Nov 1;50(22):5514-8. doi: 10.1021/jm070653r. Epub 2007 Oct 9.

Abstract

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Among the organophosphates, with the exception of soman, tabun (GA) intoxications are the least responsive to treatment with commercially available therapeutics. A rational design was used to increase reactivation ability and decrease the toxicity of the novel reactivator. (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203) has better properties than previously tested compounds in vitro and, therefore, is a potential candidate for the treatment of GA intoxication in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Chemical Warfare Agents / chemistry*
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Reactivators / chemical synthesis*
  • Cholinesterase Reactivators / chemistry
  • Drug Design
  • Kinetics
  • Organophosphates / chemistry*
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Pyridinium Compounds / chemical synthesis*
  • Pyridinium Compounds / chemistry
  • Structure-Activity Relationship

Substances

  • 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene
  • Chemical Warfare Agents
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Organophosphates
  • Oximes
  • Pyridinium Compounds
  • Acetylcholinesterase
  • tabun