Naslov
Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physico- chemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents

Autori
Zorbaz, Tamara ; Malinak, David ; Maraković, Nikola ; Maček Hrvat, Nikolina ; Zandona, Antonio ; Novotny, Michal ; Skarka, Adam ; Andrys, Rudolf ; Benkova, Marketa ; Soukup, Ondrej ; Katalinić, Maja ; Kuca, Kamil ; Kovarik, Zrinka ; Musilek, Kamil

Izvornik
Journal of Medicinal Chemistry (0022-2623) 61 (2018), 23; 10753-10766

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
organophosphorus compound, cholinesterase, antidote, pralidoxime, asoxime, chlorinated pyridinium oxime

Sažetak
Six chlorinated bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the pKa value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to non-chlorinated analogues. The nucleophilicity was examined and the pKa was found to be lower than that of analogous non- chlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the bis-chlorinated analogue of oxime K027 with significantly improved ability to reactivate the conjugated enzyme due to improved binding affinity and molecular recognition. Its overall reactivation of sarin-, VX-, and cyclosarin-inhibited AChE was respectively, three-, seven-, and eight-fold higher than by K027. Its universality, favorable acid dissociation constant coupled with its negligible cytotoxic effect and successful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an organophosphorus antidote.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA