Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A‑230 nerve agent surrogate

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F24%3A50021584" target="_blank" >RIV/62690094:18470/24:50021584 - isvavai.cz</a>

Výsledek na webu

<a href="https://link.springer.com/article/10.1007/s00204-024-03821-3" target="_blank" >https://link.springer.com/article/10.1007/s00204-024-03821-3</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00204-024-03821-3" target="_blank" >10.1007/s00204-024-03821-3</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A‑230 nerve agent surrogate

Popis výsledku v původním jazyce

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateralagencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of theChemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination,has recently included in the CWC “Annex on Chemicals” some organophosphorus compounds that are regarded asacting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase.Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterasereactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class oftoxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman’s assay to evaluate its abilityto inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes areable to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for theauthentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoximeis the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite ofthe in silico data previously disclosed.

Název v anglickém jazyce

Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A‑230 nerve agent surrogate

Popis výsledku anglicky

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateralagencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of theChemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination,has recently included in the CWC “Annex on Chemicals” some organophosphorus compounds that are regarded asacting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase.Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterasereactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class oftoxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman’s assay to evaluate its abilityto inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes areable to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for theauthentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoximeis the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite ofthe in silico data previously disclosed.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30108 - Toxicology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

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

10

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

11

Strana od-do

3397-3407

Kód UT WoS článku

001270948800002

EID výsledku v databázi Scopus

2-s2.0-85198542353