Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
38493910
DOI
10.1016/j.cbi.2024.110941
PII: S0009-2797(24)00087-5
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Butyrylcholinesterase, Nerve agents, Oxime, Pesticides, Reactivator,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes chemistry pharmacology MeSH
- Butyrylcholinesterase * metabolism chemistry MeSH
- Cholinesterase Inhibitors chemistry pharmacology MeSH
- Kinetics MeSH
- Humans MeSH
- Organophosphorus Compounds chemistry MeSH
- Organophosphate Poisoning * drug therapy MeSH
- Oximes * chemistry pharmacology MeSH
- Cholinesterase Reactivators * chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Butyrylcholinesterase * MeSH
- Cholinesterase Inhibitors MeSH
- Organophosphorus Compounds MeSH
- Oximes * MeSH
- Cholinesterase Reactivators * MeSH
The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.
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