Counteracting poisoning with chemical warfare nerve agents

Abstract

Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

“…Methamidophos and fenamiphos are phosphoramidates that already have oxo-phosphate form, which could make them effective cholinergic inhibitors similar to their analogue, a well-known nerve agent tabun 14 . To successfully prevent cholinergic crisis and avoid severe health effects after exposure to OPs, prompt dephosphylation of AChE active centre needs to be done by compounds with strong nucleophile such as an oxime group 18 , 19 . The current medically approved oxime-antidotes (Fig.…”

New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

“…Oxime therapy comprises anticonvulsants and antimuscarinics to manage symptoms prompted by poisoning manifested as salivation, tremors, respiratory paralysis, and in severe exposures, death [6,7]. Unfortunately, the current standard therapy in OP poisoning is still based on a small number of quaternary pyridinium compounds, 2-PAM, obidoxime, or HI-6, which are not universal reactivators due to the structural variability of OPs and their structural impotence in passing the brain-blood barrier (BBB) [7][8][9][10].…”

“…To improve the central nervous system (CNS) activity of oximes, our recent research was directed towards oximes with increased lipophilicity, uncharged oximes, and zwitterionic oximes with a tertiary nitrogen atom [9,10]. Even though uncharged oximes were usually proven to be much better in BBB penetration due to increased lipophilicity [11,12], their downfall is the low affinity as a consequence of the absence of a positive charge for productive interactions with the OP-inhibited enzyme [13,14].…”

“…Even though uncharged oximes were usually proven to be much better in BBB penetration due to increased lipophilicity [11,12], their downfall is the low affinity as a consequence of the absence of a positive charge for productive interactions with the OP-inhibited enzyme [13,14]. This is where the concept of a peripheral site ligand (PSL) was introduced into the oxime structure as compensation for the positively charged nitrogen in order to preserve, if not increase, the affinity for the enzyme [9,10,15,16]. The introduction of the PSL strategy, which involves the coupling of uncharged pyridine oximes with different PSLs via alkyl chains, has opened up many options for new oxime structures.…”

Calculation of the infrared spectra of organophosphorus compounds and prediction of new types of nerve agents

“…The structures of the compounds considered in the additional calculations were used as the local minimum structure through optimization. Among the 83 substances, A-242 and A-262, which were previously reported as Novichok candidates, 36 and 81 structures, in which each functional group was substituted with three types of alkyl group (methyl, ethyl, and propyl) using the A-series candidates of Novichok as the backbone, were included. The naming method for the structures substituted with alkyl groups is shown in Fig.…”