SAR Study on Reactivators of Ethyl-Paraoxon Inhibited Acetylcholinesterase

Ondrej      Holas; Kamil      Musilek; Anna      Horova; Veronika      Opletalova; Kamil      Kuca

Abstract

The current treatment of organophosphorus compounds induced intoxication consists of combined administration of anticholinergic drug, oxime reactivator and anticonvulsant. Oxime reactivators are causal treatment of organophosphorus intoxication and they are able to cleave OP moiety from the molecule of inhibited acetylcholinesterase. Unfortunately, none of the currently used oximes is sufficiently effective against all nerve agents and pesticides. Thus, finding of new potent acetylcholinesterase reactivators is necessary.

In this study, the reactivation efficacy of three series of novel bisquaternary reactivators with prop-1,3-diyl, but-1,4-diyl and but-2-ene-1,4-diyl linker against paraoxon inhibited acetylcholinesterase in vitro is presented. The obtained results were compared to the commercially used reactivators (pralidoxime, trimedoxime, obidoxime, methoxime, asoxime). Some newly prepared compounds showed promising ability of paraoxon in vitro reactivation, even in human attainable plasma concentrations. The structure-activity relationship for reactivators of paraoxon induced inhibition was determined.

Keywords: Acetylcholinesterase, Organophosphate, Paraoxon, Reactivator, Oxime, SAR

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