engleski

Potent 3-hydroxy-2-pyridine aldoxime reactivators of organophosphate-inhibited cholinesterases with predicted blood-brain barrier penetration

A new series of 3‐hydroxy‐2‐pyridine aldoxime compounds were designed, synthesized and tested in vitro, in silico and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs) (e.g., VX, sarin, cyclosarin, tabun and paraoxon). The reactivation rates of three oximes (16, 17, 18) were greater than those of 2‐PAM, and comparable to HI‐6, two pyridinium aldoximes currently used by the armies of several countries worldwide. The important interactions for a productive orientation of the oxime group within the OP‐inhibited enzyme were clarified by molecular modelling studies and by the resolution of the crystal structure of the complex of 17 with Torpedo californica AChE. The prediction of blood‐brain barrier penetration was carried out for oximes 15−18 based on their physicochemical properties and in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine‐3‐ hydroxy pyridine aldoxime conjugates showed to be promising reactivators of OP‐inhibited cholinesterases. Moreover, ex vivo efficient reactivation of phosphorylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon and cyclosarin in whole human blood implying a scavenging potential of the oximes

HI-6, pesticide, sarin, VX, acetylcholinesterase, butyrylcholinesterase, CNS active, PAMPA

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