Reversal of Tabun Toxicity Enabled by a Triazole-Annulated Oxime Library-Reactivators of Acetylcholinesterase

Chemistry. 2019 Mar 15;25(16):4100-4114. doi: 10.1002/chem.201805051. Epub 2019 Feb 14.


Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun-inhibited human AChE, and in vivo antidotal efficacies in tabun-exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds.

Keywords: acetylcholinesterase; biochemistry; heterocycles; nerve agents; organophosphate antidotes.

MeSH terms

  • Acetylcholinesterase / drug effects*
  • Alkynes / chemistry
  • Animals
  • Antibiotic Prophylaxis / methods
  • Antidotes / metabolism
  • Azides / chemistry
  • Catalysis
  • Copper / chemistry
  • Female
  • Kinetics
  • Mice
  • Molecular Structure
  • Organophosphates / chemical synthesis
  • Organophosphates / toxicity*
  • Organophosphorus Compounds / metabolism
  • Oximes / administration & dosage
  • Oximes / adverse effects
  • Oximes / pharmacokinetics*
  • Triazoles / chemistry*


  • Alkynes
  • Antidotes
  • Azides
  • Organophosphates
  • Organophosphorus Compounds
  • Oximes
  • Triazoles
  • Copper
  • Acetylcholinesterase
  • tabun