Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase

Bioorg Med Chem. 2017 Aug 15;25(16):4497-4505. doi: 10.1016/j.bmc.2017.06.041. Epub 2017 Jun 27.


A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.

Keywords: Human acetylcholinesterase; Nerve agent; Nonquaternary reactivator; Peripheral site ligand; Salicylaldoxime conjugates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Reactivators / chemical synthesis
  • Cholinesterase Reactivators / chemistry
  • Cholinesterase Reactivators / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Oximes / chemical synthesis
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Structure-Activity Relationship


  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Ligands
  • Oximes
  • salicylaldoxime
  • Acetylcholinesterase