engleski

Characterization of novel imidazolium oximes as selective reactivators of nerve agent-inhibited butyrylcholinesterase

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes crucial for neurotransmitter acetylcholine metabolism in both central and peripheral nervous system. The progressive inhibition of these enzymes by nerve agents (NA) during poisoning disrupts acetylcholine breakdown, leading to excessive impulse transmission and cholinergic crisis. Since BChE circulates freely in the bloodstream, it has been considered as a possible exogenous bioscavenging enzyme which would act as an oxime- assisted catalytic scavenger of NAs, neutralising them before they reach target tissues. Oximes are used in standard clinical therapy to recover activity of inhibited cholinesterases, but reactivating BChE with standard pyridinium oximes proved to be ineffective as they are mainly AChE reactivators. To approach this issue, based on previous research we synthesized eight novel N- benzyl supstituted imidazolium oximes to be considered as reactivators of nerve agent sarin-, cyclosarin- and tabun-inhibited human AChE and BChE. Two oximes emerged as effective reactivators of all three NA-BChE conjugates, possessing superior overall reactivation rates (kr) than standard oxime HI-6 which was up to 3000-times higher for cyclosarin conjugate and 210-times for sarin conjugate, or 100-times higher than oxime TMB-4 in case of tabun conjugate. Binding affinities of phosphylated BChE for novel oximes in terms of 1/KOX increased up to 1900-fold compared to standard oximes and they achieved their reactivation maximum in a shorter time frame. However, standard pyridinium oximes remain better reactivators of phosphylated AChE which indicates that imidazolium oximes with 1, 3- aromatic substituents do not position optimally into the AChE active site gorge. Novel oximes' low toxicity on hepatic (HepG2) and neuronal (SH-SY5Y) cell lines and high capacity for reactivation of BChE in the studied concentration range establishes them as promising candidates for future treatment development.

acetylcholinesterase, butyrylcholinesterase, bioscavenging, nerve agents, imidazole oximes

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