Pralidoxime-like reactivator with increased lipophilicity - Molecular modeling and in vitro study

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore A...

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Bibliographic Details
Published in:Chemico-biological interactions 2023-11, Vol.385, p.110734-110734, Article 110734
Main Authors: Kuca, Kamil, Valle da Silva, Jorge Alberto, Nepovimova, Eugenie, Pham, Ngoc Lam, Wu, Wenda, Valis, Martin, Wu, Qinghua, França, Tanos Celmar Costa
Format: Article
Language:English
Subjects:
2-PAM
Antidote
Nerve agent
Pesticide
Reactivator
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Summary:Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator. •Commercially available AChE reactivators poorly penetrate into the brain.•Increasing the lipophilicity of reactivators might improve BB penetration.•2-PAM lipophilicity was increased through incorporation of a benzyl group into its structure.•Such structure modification decreased its reactivation potency face several nerve agents.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2023.110734