Design, Chemical Synthesis, and In Vitro Evaluation of Novel Uncharged Cholinesterase Reactivator

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F26%3A00566668" target="_blank" >RIV/60162694:G44__/26:00566668 - isvavai.cz</a>

Výsledek na webu

<a href="https://mmsl.cz/artkey/mms-202504-0001_design-chemical-synthesis-and-in-vitro-evaluation-of-novel-uncharged-cholinesterase-reactivator.php" target="_blank" >https://mmsl.cz/artkey/mms-202504-0001_design-chemical-synthesis-and-in-vitro-evaluation-of-novel-uncharged-cholinesterase-reactivator.php</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.31482/mmsl.2024.015" target="_blank" >10.31482/mmsl.2024.015</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, Chemical Synthesis, and In Vitro Evaluation of Novel Uncharged Cholinesterase Reactivator

Popis výsledku v původním jazyce

The primary toxicological mechanism of organophosphorus compounds (OPCs) is the irreversible inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine and subsequent cholinergic crisis, which can result in fatal respiratory failure. Conventional oxime reactivators, such as pralidoxime and obidoxime, are limited by their inability to permeate the blood-brain barrier (BBB) and inconsistent efficacy across different OPC types. To address these limitations, we designed a novel non-quaternary oxime reactivator codenamed K1396, with enhanced lipophilicity for improved BBB penetration and dual-binding capability at both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. This study compares the in vitro reactivation potency, cytotoxicity, and BBB penetration potential of K1396 with standard oximes. K1396 demonstrated comparable or superior reactivation potency, particularly against VX-inhibited AChE, and showed lower cytotoxicity in specific cell lines. Furthermore, K1396 exhibited favorable permeability across the lipid layer, suggesting potential CNS availability. The findings support the therapeutic potential of K1396 as an effective and broad-spectrum reactivator for OPC poisoning.

Název v anglickém jazyce

Design, Chemical Synthesis, and In Vitro Evaluation of Novel Uncharged Cholinesterase Reactivator

Popis výsledku anglicky

The primary toxicological mechanism of organophosphorus compounds (OPCs) is the irreversible inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine and subsequent cholinergic crisis, which can result in fatal respiratory failure. Conventional oxime reactivators, such as pralidoxime and obidoxime, are limited by their inability to permeate the blood-brain barrier (BBB) and inconsistent efficacy across different OPC types. To address these limitations, we designed a novel non-quaternary oxime reactivator codenamed K1396, with enhanced lipophilicity for improved BBB penetration and dual-binding capability at both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. This study compares the in vitro reactivation potency, cytotoxicity, and BBB penetration potential of K1396 with standard oximes. K1396 demonstrated comparable or superior reactivation potency, particularly against VX-inhibited AChE, and showed lower cytotoxicity in specific cell lines. Furthermore, K1396 exhibited favorable permeability across the lipid layer, suggesting potential CNS availability. The findings support the therapeutic potential of K1396 as an effective and broad-spectrum reactivator for OPC poisoning.

Druh

J_ost - Ostatní články v recenzovaných periodicích

CEP obor

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OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Military Medical Science Letters

ISSN

2571-113X

e-ISSN

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Svazek periodika

94

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

CZ - Česká republika

Počet stran výsledku

11

Strana od-do

135-145

Kód UT WoS článku

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EID výsledku v databázi Scopus

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