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Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase
Author(s) -
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
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201805051
Subject(s) - tabun , chemistry , nerve agent , oxime , acetylcholinesterase , phosphoramidate , cholinesterase , pharmacology , combinatorial chemistry , stereochemistry , biochemistry , enzyme , biology
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.