Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A-230 nerve agent surrogate.

Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0417615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0738 (Electronic) Linking ISSN: 03405761 NLM ISO Abbreviation: Arch Toxicol Subsets: MEDLINE

Original Publication: Berlin, New York, Springer-Verlag.

Oximes*/pharmacology ; Acetylcholinesterase*/metabolism ; Cholinesterase Reactivators*/pharmacology ; Cholinesterase Inhibitors*/toxicity ; Pyridinium Compounds*/pharmacology ; Chemical Warfare Agents*/toxicity ; Nerve Agents*/toxicity; Pralidoxime Compounds/pharmacology ; Organothiophosphorus Compounds/toxicity ; Animals ; Antidotes/pharmacology

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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Keywords: A-230; Acetylcholinesterase; Antidotes; Chemical Weapons Convention; Nerve agent surrogates

0 (Oximes)
EC 3.1.1.7 (Acetylcholinesterase)
0 (Cholinesterase Reactivators)
0 (Cholinesterase Inhibitors)
0 (Pyridinium Compounds)
0 (Chemical Warfare Agents)
0 (Nerve Agents)
0 (Pralidoxime Compounds)
0 (Organothiophosphorus Compounds)
P7MU9UTP52 (pralidoxime)
0 (Antidotes)

Date Created: 20240714 Date Completed: 20240915 Latest Revision: 20241209

20241210

10.1007/s00204-024-03821-3

39004640