engleski

In vitro evaluation of quinuclidinium oximes as reactivators of organophosphorus compounds inhibited human cholinesterases

In this study we focused on evaluation of the use of quinuclidinium oximes as potential antidotes in organophosphorus compounds (OPs) poisoning. We determined reversible inhibition of human red blood cell acetylcholinesterase (AChE) and human plasma butyrylcholinesterase (BChE) by 14 quinuclidinium oximes and reactivation of tabun-, VX-, paraoxon-, sarin- and cyclosarin-inhibited enzymes. Reversible inhibition constants were in the range spreading from 3 μM to 4 mM, depending on the oxime structure. The highest inhibition was observed for Q5 which has long aliphatic chain on the quinuclidinium ring quaternary nitrogen. It seems that AChE is selective to oximes that have groups in meta position on the benzene ring while BChE to those with group in para position. Quinuclidinium potency to reactivate organophosphorus-inhibited cholinesterases in vitro, proved promising in restoring cholinesterases activity. VX- and paraoxon- inhibited AChE were reactivated by several candidates up to 90 - 100 % within 1 - 4 hours. Oximes with group in para position showed reactivation potency for cyclosarin-inhibited BChE with reactivation up to 90 - 100 %. Furthermore, at the very beginning of the antidote development, we investigated if quinuclidinium oximes are cytotoxic on selected cell lines. As results indicate, quinuclidinium oximes didn’t show cytotoxic profiles up to 800 μM. Exception was observed only for Q5, oxime with long aliphatic chain in the structure, influencing cells vitality at concentrations significant for reactivation of cholinesterases. Acknowledgment: This work was supported by the Croatian Science Foundation grant no. 4307 and UIP-2017-05-7260.

quinuclidinium ; organophosphorus ; oximes ; reactivation

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