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

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

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
16th Medical Chemical Defence Conference ˝100 years after the first use of sulfur mustard - re-emerging threats of chemical warfare agents and current state of medical research˝ / - München, 2017

Skup
16th Medical Chemical Defence Conference ˝100 years after the first use of sulfur mustard - re-emerging threats of chemical warfare agents and current state of medical research˝

Mjesto i datum
München, Njemačka, 05.04.2017. - 06.04.2017

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
nerve agents, AChE, BChE, uncharged reactivators

Sažetak
Intoxication by organophosphorus nerve agents (OPNA) leads to the irreversible inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This inhibition causes acetylcholine accumulation in the peripheral and central nervous system synapses, leading to a cholinergic crisis. 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 (2-PAM, HI-6, LüH-6, TMB- 4) 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, hydrogen bond donors and acceptors, pKa) 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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA