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 p Ka 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 p Ka 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.
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Authors | Tamara Zorbaz, David Malinak, Nikola Maraković, Nikolina Maček Hrvat, Antonio Zandona, Michal Novotny, Adam Skarka, Rudolf Andrys, Marketa Benkova, Ondrej Soukup, Maja Katalinić, Kamil Kuca, Zrinka Kovarik, Kamil Musilek |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 61
Issue 23
Pg. 10753-10766
(12 13 2018)
ISSN: 1520-4804 [Electronic] United States |
PMID | 30383374
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cholinesterase Inhibitors
- Cholinesterase Reactivators
- Nerve Agents
- Oximes
- Chlorine
- Acetylcholinesterase
- Butyrylcholinesterase
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Topics |
- Acetylcholinesterase
(chemistry, metabolism)
- Butyrylcholinesterase
(metabolism)
- Cell Line, Tumor
- Chemical Phenomena
- Chlorine
(chemistry)
- Cholinesterase Inhibitors
(pharmacology)
- Cholinesterase Reactivators
(chemical synthesis, chemistry, metabolism, pharmacology)
- Humans
- Isomerism
- Molecular Docking Simulation
- Nerve Agents
(pharmacology)
- Oximes
(chemical synthesis, chemistry, metabolism, pharmacology)
- Protein Conformation
- Structure-Activity Relationship
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