Novel Group of AChE Reactivators-Synthesis, In Vitro Reactivation and Molecular Docking Study.

David Malinak,Kamil Kuca,Eugenie Nepovimova,Kamil Musilek,Daniel Jun

doi:10.3390/molecules23092291

Abstract

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.

Highlights

Organophosphorus agents (OP) are among the most toxic compounds developed by humans.They were originally discovered as pesticides, but they were further introduced as nerve agents, with highly lethal effects [1]
The molecular modelling study was performed with oximes 3, 9 and 23 to rationalize their interactions with GA-inhibited HssAChE [29]
Oxime 23 was selected as the best reactivator of GA-induced toxicity in vitro from among the newly prepared compounds

Summary

Introduction

Organophosphorus agents (OP) are among the most toxic compounds developed by humans.They were originally discovered as pesticides (e.g., paraoxon, methylparaoxon; Figure 1), but they were further introduced as nerve agents (e.g., tabun, sarin, soman, VX; Figure 1), with highly lethal effects [1]. Organophosphorus agents (OP) are among the most toxic compounds developed by humans. Some OPs are utilized as industrial agents (e.g., flame retardants). Their mechanism of action is based on the irreversible inhibition of cholinesterases [2]. Acetylcholine is accumulated in the synapses, causing permanent stimulation of the cholinergic (muscarinic or nicotinic) receptors. For this reason, cholinergic symptoms (e.g., miosis, salivation, lacrimation, breath depression) occur that may worsen to cholinergic crisis or death from the malfunction of breathing muscles and the depression of the breathing center in the central nervous system [4]

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Conclusion