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

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 react...

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Bibliographic Details
Published in:Chemistry : a European journal 2019-03, Vol.25 (16), p.4100-4114
Main Authors: Kovarik, Zrinka, Kalisiak, Jarosław, Hrvat, Nikolina Maček, Katalinić, Maja, Zorbaz, Tamara, Žunec, Suzana, Green, Carol, Radić, Zoran, Fokin, Valery V., Sharpless, K. Barry, Taylor, Palmer
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Activation
Alkynes
Antidotes
biochemistry
Biocompatibility
Biological & chemical weapons
Chemistry
Exposure
heterocycles
Nerve agents
organophosphate antidotes
Organophosphorus compounds
Oximes
Pesticides
Prophylaxis
Pyridinium
Tabun
Toxicity
Triazoles
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Summary: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. Developing antidotes: A substantial number of N‐methylpyridinium and 2‐methylimidazolium oximes that show significantly improved in vitro reactivating efficacies for tabun‐inhibited AChE have been synthesized and pharmacologically characterized. These findings offer a valuable and comprehensive platform for further development of antidotes and scavengers against tabun and related phosphoramidate exposures.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201805051