A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Kamil Kuca,Alexandre A De Castro,Eugenie Nepovimova,Kamil Musilek,John Mikler,Ondrej Soukup,Tanos C C Franca,Elaine F F Da Cunha,Teodorico C Ramalho,Martin Valis,Jana Zdarova-Karasova,Daniel Jun,Martina Hrabinova

doi:10.1186/s40360-018-0196-3

Abstract

BackgroundBased on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes.MethodsTo determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6).ResultsReactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min− 1. M− 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min− 1. M− 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE.DiscussionAccording to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

Highlights

Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes
The the current study demonstrates the efficacy of K203 reactivation of tabuninhibited AChE in human brain homogenate
Chemicals K203 ((E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide) was prepared at Source of human brain cholinesterase The nucleus caudatus was obtained from autopsy patient material aged 68 and 70, who died by accident (Department of Forensic Medicine, Faculty of Medicine in Hradec Kralove, Charles University In Prague)

Summary

Introduction

Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. Tabun’s extraordinary toxicity and resistance to current medical countermeasures appear to be the result of inhibition of acetylcholinesterase (AChE), which is difficult to reactivate due to the presence of a lone electron pair on the amidic group [7]. In 2003, two new oximes aimed at the reactivation of tabunintoxications, K027 and K048 were developed [14, 15] They differ from the chemical structure of trimedoxime and obidoxime, which are symmetric compounds, and a carbamoyl group was introduced into their structure to

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