Vše

Co hledáte?

Vše
Projekty
Výsledky výzkumu
Subjekty

Rychlé hledání

  • Projekty podpořené TA ČR
  • Významné projekty
  • Projekty s nejvyšší státní podporou
  • Aktuálně běžící projekty

Chytré vyhledávání

  • Takto najdu konkrétní +slovo
  • Takto z výsledků -slovo zcela vynechám
  • “Takto můžu najít celou frázi”

Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F22%3A50019310" target="_blank" >RIV/62690094:18470/22:50019310 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/00179906:_____/22:10445593

  • Výsledek na webu

    <a href="https://www.sciencedirect.com/science/article/pii/S0223523422002793?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523422002793?via%3Dihub</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.ejmech.2022.114377" target="_blank" >10.1016/j.ejmech.2022.114377</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents

  • Popis výsledku v původním jazyce

    The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fluorinated &lt; chlorinated &lt; non-halogenated) along with higher level of oximate anion formation at the physiological pH, and had a higher binding affinity of both AChE and BChE. The stability tests showed that the fluorinated oximes were stable in water, while in buffered environment di-fluorinated oximes were prone to rapid degradation, which was reflected in their lower reactivation ability. Mono-fluorinated oximes showed comparable reactivation to non-halogenated (except asoxime) and mono-chlorinated oximes in case of AChE inhibited by sarin, cyclosarin, VX, and tabun, but were less efficient than di-chlorinated ones. The same trend was observed in the reactivation of inhibited BChE. The advantage of halogen substituents in the stabilization of oxime in a position optimal for in-line nucleophilic attack were confirmed by extensive molecular modelling of pre-reactivation complexes between the analogue oximes and phosphorylated AChE and BChE. Halogen substitution was shown to provide oximes with additional beneficial properties, e.g., fluorinated oximes gained antioxidative capacity, and moreover, halogens themselves did not increase cytotoxicity of oximes. Finally, the in vivo administration of highly efficient reactivator and the most promising analogue, 3,5-di-chloro-bispyridinium oxime with trimethylene linker, provided significant protection of mice exposed to sarin and cyclosarin.

  • Název v anglickém jazyce

    Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents

  • Popis výsledku anglicky

    The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fluorinated &lt; chlorinated &lt; non-halogenated) along with higher level of oximate anion formation at the physiological pH, and had a higher binding affinity of both AChE and BChE. The stability tests showed that the fluorinated oximes were stable in water, while in buffered environment di-fluorinated oximes were prone to rapid degradation, which was reflected in their lower reactivation ability. Mono-fluorinated oximes showed comparable reactivation to non-halogenated (except asoxime) and mono-chlorinated oximes in case of AChE inhibited by sarin, cyclosarin, VX, and tabun, but were less efficient than di-chlorinated ones. The same trend was observed in the reactivation of inhibited BChE. The advantage of halogen substituents in the stabilization of oxime in a position optimal for in-line nucleophilic attack were confirmed by extensive molecular modelling of pre-reactivation complexes between the analogue oximes and phosphorylated AChE and BChE. Halogen substitution was shown to provide oximes with additional beneficial properties, e.g., fluorinated oximes gained antioxidative capacity, and moreover, halogens themselves did not increase cytotoxicity of oximes. Finally, the in vivo administration of highly efficient reactivator and the most promising analogue, 3,5-di-chloro-bispyridinium oxime with trimethylene linker, provided significant protection of mice exposed to sarin and cyclosarin.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30108 - Toxicology

Návaznosti výsledku

  • 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)

Ostatní

  • Rok uplatnění

    2022

  • Kód důvěrnosti údajů

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

Údaje specifické pro druh výsledku

  • Název periodika

    European Journal of Medicinal Chemistry

  • ISSN

    0223-5234

  • e-ISSN

    1768-3254

  • Svazek periodika

    238

  • Číslo periodika v rámci svazku

    August

  • Stát vydavatele periodika

    FR - Francouzská republika

  • Počet stran výsledku

    16

  • Strana od-do

    "Article Number: 114377"

  • Kód UT WoS článku

    000804189700002

  • EID výsledku v databázi Scopus

    2-s2.0-85129289597