Author/Editor		Zorbaz, Tamara; Malinak, David; Maraković, Nikola; Maček Hrvat, Nikolina; Zandona, Antonio; Novotný, Michal; Skarka, Adam; Andrys, Rudolf; Benkova, Marketa; Soukup, Ondrej
Title		Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physicochemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents
Type		članek
Vol. and No.		Letnik 61, št. 23
Publication year		2018
Volume		str. 10753-10766
ISSN		0022-2623 - Journal of medicinal chemistry
Language		eng
Abstract		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 pKavalue of the oxime group, thus resulting in ahigher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the pKawas found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated humanAChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated analogue of oxime K027 withsignificantly 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, 3-, 7-, and 8-fold higher than by K027. Itsuniversality, PAMPA permeability, favorable acid dissociation constant coupled with its negligible cytotoxic effect, andsuccessful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an antidote fororganophosphorus poisoning.
Keywords		acetylcholinesterase reactivators chlorinated bispyridinium mono-oxime acetilholinesteraza reaktivatorji klorirani bispiridinijevi mono-oksimi