Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents

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 pK a value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated ana...

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Published inJournal of medicinal chemistry Vol. 61; no. 23; pp. 10753 - 10766
Main Authors 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
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.12.2018
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
BISPYRIDINIUM OXIMES
TABUN
CURRENTLY USED OXIMES
IN-VITRO
UNCHARGED REACTIVATORS
OBIDOXIME
RAT-BRAIN ACETYLCHOLINESTERASE
K203
FLUORINATED ANALOG KR-22836
HI-6
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Summary: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 pK a value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the pK a was found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated 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, 3-, 7-, and 8-fold higher than by K027. Its universality, PAMPA permeability, 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 antidote for organophosphorus poisoning.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01398