Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication.

Autor: Gorecki L; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: lukas.gorecki@unob.cz., Markova A; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Hospital Pharmacy, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Hepnarova V; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Zivna N; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Junova L; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic., Hrabinova M; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Janousek J; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Kobrlova T; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Prchal L; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Jun D; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic., Soukup O; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic., Horn G; Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany., Worek F; Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany., Marek J; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; University of Defence, Military Faculty of Medicine, Department of Epidemiology, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic., Korabecny J; University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 May 01; Vol. 394, pp. 110941. Date of Electronic Publication: 2024 Mar 16.
DOI: 10.1016/j.cbi.2024.110941
Abstrakt: 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.
Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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