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Pregled bibliografske jedinice broj: 968337

Zbornik radova

Autori: Zorbaz, Tamara; Mišetić, Petra; Maraković, Nikola; Zandona, Antonio; Katalinić, Maja; Maček Hrvat, Nikolina; Braiki, Anissa; Gabelica Marković, Vesna; Jean, Ludovic; Renard, Pierre-Yves; Kovarik, Zrinka
Naslov: Potent lipophilic 3-hydroxy-2-pyridinium aldoxime reactivators of phosphorylated cholinesterases
( Potent lipophilic 3-hydroxy-2-pyridinium aldoxime reactivators of phosphorylated cholinesterases )
Izvornik: Arhiv za higijenu rada i toksikologiju Vol. 69(3)
ISSN: 0004-1254
Skup: Workshop on "Reactivators and Medical Countermeasures against Nerve Agents and Pesticides”
Mjesto i datum: Zagreb, Hrvatska, 14-15.5.2018.
Ključne riječi: AChE, CNS, molecular docking, nerve agents, oximes, synthesis
( AChE, CNS, molecular docking, nerve agents, oximes, synthesis )
Sažetak:
Organophosphate compounds (OPs) poisoning can occur due to exposure to OP pesticides (e.g., parathion) or nerve agents (e.g., sarin, cyclosarin, VX, tabun). OPs irreversibly inhibit acetylcholinesterase (AChE) causing the accumulation of acetylcholine in synapses and cholinergic crisis, which can lead to respiratory arrest and death or result in long- term neurological impairments in survivors. Reactivation of OP-inhibited AChE is one of the possible therapy approaches, but standard oxime reactivators (2- PAM, HI-6, obidoxime) are not potent enough for every OP and achieve low brain concentrations due to a permanent charge (quaternary nitrogen). New class of oximes, 3- hydroxy-2-pyridine aldoximes, without permanent charge have been synthesized and tested in detail. They were proven to be potent reactivators of AChE inhibited by VX, sarin, cyclosarin, tabun, and paraoxon with the affinity of AChE in the micromolar range. Moreover, molecular docking studies predicted optimal orientation of the oximes in the active site of OP-inhibited AChE. Furthermore, these oximes were proven to be lipophilic and by analysing various physicochemical properties that describe their size, charge, lipophilicity, and polarity we predicted their penetration through the blood-brain barrier (BBB). The permeability of these oximes across the membrane was confirmed in vitro using an artificial membrane that mimics the BBB. In addition, most of the oximes were shown to be metabolically stable when incubated with human microsomes and were not cytotoxic for neuroblastoma and astrocytoma cell lines. Finally, the lead oxime crossed the BBB in vivo in mice after intramuscular application proving its potential to be used as a centrally active antidote.
Rad je indeksiran u
bazama podataka:
MEDLINE
Scopus
SCI-EXP, SSCI i/ili A&HCI
Science Citation Index Expanded (SCI-EXP) (sastavni dio Web of Science Core Collectiona)
Vrsta sudjelovanja: Predavanje
Vrsta prezentacije u zborniku: Sažetak
Vrsta recenzije: Domaća recenzija
Projekt / tema: HRZZ-IP-2013-11-4307, HRZZ-UIP-2017-05-7260
Izvorni jezik: eng
Kategorija: Znanstveni
Znanstvena područja:
Kemija
URL Internet adrese: https://hrcak.srce.hr/206044
Upisao u CROSBI: Tamara Zorbaz (tzorbaz@imi.hr), 16. Stu. 2018. u 12:21 sati



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