Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

Tamara Zorbaz, Anissa Braïki, Nikola Maraković, Julien Renou, Eugenio de la Mora, Nikolina Maček Hrvat, Maja Katalinić, Israel Silman, Joel L. Sussman, Guillaume Mercey, Catherine Gomez, Romain Mougeot, Belén Pérez, Rachid Baati, Florian Nachon, Martin Weik, Ludovic Jean, Zrinka Kovarik, Pierre Yves Renard

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16–18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood–brain barrier penetration was predicted for oximes 15–18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.
Original languageEnglish
Pages (from-to)9675-9691
JournalChemistry - A European Journal
Volume24
Issue number38
DOIs
Publication statusPublished - 5 Jul 2018

Keywords

  • X-ray diffraction
  • enzymes
  • molecular modeling
  • organophosphates
  • oximes

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