Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration.
作者： Tamara Zorbaz , Anissa Braïki , Nikola Maraković , Julien Renou , Eugenio de la Mora
关键词: Chemistry 、 Cyclosarin 、 Tabun 、 Sarin 、 Oxime 、 Stereochemistry 、 Paraoxon 、 Butyrylcholinesterase 、 Acetylcholinesterase 、 Organophosphate
摘要: A new series of 3‐hydroxy‐2‐pyridine aldoxime compounds have been designed, synthesised and tested in vitro, silico, ex vivo as reactivators human acetylcholinesterase (hAChE) butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, paraoxon. The reactivation rates three oximes (16–18) were determined to be greater than that 2‐PAM comparable HI‐6, two pyridinium aldoximes currently used the armies several countries. interactions important a productive orientation oxime group within OP‐inhibited enzyme clarified molecular‐modelling studies, resolution crystal structure complex 17 with Torpedo californica AChE. Blood–brain barrier penetration was predicted 15–18 based on their physicochemical properties an vitro brain membrane permeation assay. Among evaluated compounds, morpholine‐3‐hydroxypyridine conjugates proved promising cholinesterases. Moreover, efficient phosphylated native cholinesterases selected enabled significant hydrolysis paraoxon, cyclosarin whole blood, which indicates scavenging potential.
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