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New uncharged potent reactivators of AChE and BChE inhibited by nerve agents (CROSBI ID 671442)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa

Zorbaz, Tamara ; Braiki, Anissa ; Maraković, Nikola ; Katalinić, Maja ; Renou, Julien ; Jean, Ludovic ; Renard, Pierre-Yves ; Kovarik, Zrinka New uncharged potent reactivators of AChE and BChE inhibited by nerve agents // Knjiga sažetaka Drugog Simpozija studenata doktorskih studija PMF-a 2017./2018.. 2018. str. 8-8

Podaci o odgovornosti

Zorbaz, Tamara ; Braiki, Anissa ; Maraković, Nikola ; Katalinić, Maja ; Renou, Julien ; Jean, Ludovic ; Renard, Pierre-Yves ; Kovarik, Zrinka

engleski

New uncharged potent reactivators of AChE and BChE inhibited by nerve agents

Intoxication by organophosphorus nerve agents (OPNA ; e.g. sarin, cyclosarin, tabun, VX) leads to the irreversible inhibition of enzymes acetylcholinesterase (AChE, E.C. 3.1.1.7.) and butyrylcholinesterase (BChE, E.C. 3.1.1.8). This inhibition causes acetylcholine accumulation in the peripheral and central nervous system synapses, leading to a cholinergic crisis (miosis, headache, dyspnoea, ocular impairments, excessive secretion, fasciculations, etc.). The most prominent symptoms with a possible lethal outcome are respiratory failure and seizures, but those who survive can also experience long-term neurological impairments, e.g. cognitive and behavioural incapacitations. The antidote treatment comprises an antimuscarinic drug, an oxime reactivator and an anticonvulsive drug. Standard reactivators (e.g. 2-PAM, HI-6, LüH-6) are not efficient for every OPNA, and since they have positively charged quaternary nitrogen in their structures, they cross the brain-blood barrier poorly. We synthesised and evaluated novel uncharged and therefore possibly centrally active reactivators. They showed a highly promising in vitro reactivation profile for VX-inhibited AChE/BChE, sarin- inhibited AChE and cyclosarin-inhibited BChE. Using molecular docking, the possible interactions that these oximes form with the amino acid residues in the active site gorge of the enzymes near the covalently linked OPNA, were detected. Additionally, in silico determined physicochemical properties (e.g. lipophilicity, polar surface area, number of hydrogen bond donors and acceptors, rotatable bonds, pKa values) implied that these novel oximes were likely to be centrally active. On the other side, the higher lipophilicity was connected with a higher probability of accumulation in different tissues and therefore could have led to adverse effects. Further evaluation of these novel reactivators’ in vivo efficacy is needed, as well as evaluations of their pharmacokinetic and toxicological profiles. Acknowledgment: This work was supported by the COGITO Croatian-French bilateral grant (2015- 2016 ; PIs: Z. Kovarik and L. Jean) and by the Croatian Science Foundation (4307, PI: Z. Kovarik).

organophosphate poisoning, uncharged lipophilic oximes, centrally active reactivators

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Podaci o prilogu

8-8.

2018.

objavljeno

Podaci o matičnoj publikaciji

Knjiga sažetaka Drugog Simpozija studenata doktorskih studija PMF-a 2017./2018.

Podaci o skupu

Drugi Simpozij studenata doktorskih studija PMF-a 2017./2018.

predavanje

09.02.2018-09.02.2018

Zagreb, Hrvatska

Povezanost rada

Farmacija, Interdisciplinarne prirodne znanosti, Javno zdravstvo i zdravstvena zaštita, Kemija

Poveznice