Naslov
Chlorinated pyridinium oximes are potent reactivators of acetylcholinesterase inhibited by nerve agents

Autori
Zorbaz, Tamara ; Maraković, Nikola ; Musilek, Kamil ; Kovarik, Zrinka

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

Izvornik
Programme and Abstract Book, Military Medical Science Letters - Special Issue on the occasion of the 13th International Meeting on Cholinesterases and the 7th International Conference on Paraoxonases, Hradec Králové, Republika Češka, 2018 / Korábečný, Jan ; Soukup, Ondrej - Hradec Kralove : University of Defence, Faculty of Military Health Sciences, Czech Republic, 2018, 78-78

Skup
13th International Meeting on Cholinesterases ; 7th International Conference on Paraoxonases

Mjesto i datum
Hradec Králové, Češka Republika, 09.09.2018. - 14.09.2018

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
organophosphates, antidotes, HI-6, 2-PAM

Sažetak
Chlorinated bispyridinium aldoximes (Cl-oximes) analogous to previously reported efficient reactivators of inhibited AChE (K027, K048, K203) were designed and synthesized with the premise that the addition of a chlorine atom increases their lipophilicity in comparison to the reference oximes and that they could therefore achieve higher brain concentrations than the ones reported for non-chlorinated analogues. The affinity of hAChE for Cl-oximes was moderate, but higher than for analogous non-chlorinated oximes, as well as higher than the affinity of hBChE for Cl-oximes. Their reactivation efficacy for nerve agent-inhibited AChE was in the following order: cyclosarin>VX>sarin>tabun. Predictably, the electron-withdrawing effect of the chlorine atom led to a lower pKa value of the oxime groups as confirmed by UV/VIS measurements. Finally, using the molecular modelling approach we attempted to attribute the differences in the predicted binding modes of the tested oximes to their observed reactivity. As molecular docking results suggested, the non- bonding interactions between the chlorine atoms and neighbouring amino acid residues play a significant role in the stabilization of Cl- oximes in a productive conformation in the case of cyclosarin-inhibited AChE. Acknowledgment: This work was supported by the Croatian Science Foundation (no. 4307) and the Grant Agency of the Czech Republic (no. 18- 01734S).

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Javno zdravstvo i zdravstvena zaštita, Farmacija

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