Monooxime‐monocarbamoyl Bispyridinium Xylene‐Linked Reactivators of Acetylcholinesterase—Synthesis,In vitro and Toxicity Evaluation,and Docking Studies |
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| Authors: | Kamil Musilek Dr Ondrej Holas Jan Misik Miroslav Pohanka Dr Ladislav Novotny Vlastimil Dohnal Dr Veronika Opletalova Kamil Kuca Dr |
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| Affiliation: | 1. Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, Hradec Kralove (Czech Republic), Fax: (+42)?495‐518‐094;2. Department of Chemistry, Faculty of Science, University of Jan Evangelista Purkyne, Ceske mladeze 8, 400 96 Usti nad Labem (Czech Republic);3. Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove (Czech Republic);4. Centre of Advanced Studies, Faculty of Military Health Sciences, Trebesska 1575, Hradec Kralove (Czech Republic) |
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| Abstract: | Acetylcholinesterase (AChE) reactivators are crucial antidotes to organophosphate intoxication. A new series of 26 monooxime‐monocarbamoyl xylene‐linked bispyridinium compounds was prepared and tested in vitro, along with known reactivators (pralidoxime, HI‐6, obidoxime, trimedoxime, methoxime, K107, K108 and K203), on a model of tabun‐ and paraoxon‐, methylparaoxon‐ and DFP‐inhibited human erythrocyte AChE. Although their ability to reactivate tabun‐inhibited AChE did not exceed that of the previously known compounds, some newly prepared compounds showed promising reactivation of pesticide‐inhibited AChE. The acute toxicity of the novel compounds was also determined. Docking studies using tabun‐inhibited AChE were performed for three compounds of interest. The structure–activity relationship (SAR) study confirmed the apparent influence of the xylene linkage and carbamoyl moiety on the reactivation ability and toxicity of the agents. |
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| Keywords: | acetylcholinesterases molecular modeling organophosphates reactivators tabun |
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