New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5743-5748. doi: 10.1016/j.bmcl.2014.10.055. Epub 2014 Oct 22.

Abstract

Herein, we described a new class of uncharged non-pyridinium reactivators for nerve agent-inhibited acetylcholinesterase (AChE). Based on a dual site binding strategy, we conjugated the imidazolium aldoxime to different peripheral site ligands (PSLs) of AChE through alkyl chains. Compared with the known quaternary pyridinium reactivators, two of the resulting conjugates (7g and 7h) were highlighted to be the first efficient non-pyridinium oxime conjugates exhibiting similar or superior ability to reactivate sarin-, VX- and tabun-inhibited AChE. Moreover, they were more broad-spectrum reactivators.

Keywords: Human acetylcholinesterase; Imidazolium aldoxime; Nerve agent; Peripheral site ligand; Reactivator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Binding Sites
  • Chemical Warfare Agents / chemistry*
  • Cholinesterase Reactivators / chemical synthesis
  • Cholinesterase Reactivators / chemistry*
  • Cholinesterase Reactivators / metabolism
  • Humans
  • Imidazoles / chemistry
  • Kinetics
  • Ligands
  • Molecular Docking Simulation
  • Oximes / chemical synthesis
  • Oximes / chemistry*
  • Oximes / metabolism
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Chemical Warfare Agents
  • Cholinesterase Reactivators
  • Imidazoles
  • Ligands
  • Oximes
  • imidazole
  • Acetylcholinesterase
  • acetaldehyde oxime