Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F24%3A50021654" target="_blank" >RIV/62690094:18470/24:50021654 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/24:10484025 RIV/60162694:G44__/25:00563523

Výsledek na webu

<a href="https://link.springer.com/article/10.1007/s00204-024-03791-6" target="_blank" >https://link.springer.com/article/10.1007/s00204-024-03791-6</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00204-024-03791-6" target="_blank" >10.1007/s00204-024-03791-6</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents

Popis výsledku v původním jazyce

Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.

Název v anglickém jazyce

Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents

Popis výsledku anglicky

Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA21-03000S" target="_blank" >GA21-03000S: Modifikované nukleofily pro reaktivaci cholinesteras inhibovaných organofosforovými sloučeninami</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Archives of toxicology

ISSN

0340-5761

e-ISSN

1432-0738

Svazek periodika

98

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

16

Strana od-do

2937-2952

Kód UT WoS článku

001234052300001

EID výsledku v databázi Scopus

2-s2.0-85194353602