Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Chemical Phenomena MeSH
- Chlorine chemistry MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Isomerism MeSH
- Protein Conformation MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nerve Agents pharmacology MeSH
- Oximes chemical synthesis chemistry metabolism pharmacology MeSH
- Cholinesterase Reactivators chemical synthesis chemistry metabolism pharmacology MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Chlorine MeSH
- Cholinesterase Inhibitors MeSH
- Nerve Agents MeSH
- Oximes MeSH
- Cholinesterase Reactivators MeSH
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.
References provided by Crossref.org
Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents
Strategies for enhanced bioavailability of oxime reactivators in the central nervous system
Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
