Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
38493910
DOI
10.1016/j.cbi.2024.110941
PII: S0009-2797(24)00087-5
Knihovny.cz E-zdroje
- Klíčová slova
- Acetylcholinesterase, Butyrylcholinesterase, Nerve agents, Oxime, Pesticides, Reactivator,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota chemie farmakologie MeSH
- butyrylcholinesterasa * metabolismus chemie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- organofosforové sloučeniny chemie MeSH
- otrava organofosfáty * farmakoterapie MeSH
- oximy * chemie farmakologie MeSH
- reaktivátory cholinesterasy * chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- antidota MeSH
- butyrylcholinesterasa * MeSH
- cholinesterasové inhibitory MeSH
- organofosforové sloučeniny MeSH
- oximy * MeSH
- reaktivátory cholinesterasy * 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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