Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

Chembiochem : a European Journal of Chemical Biology
Francine S KatzMilan N Stojanovic

Abstract

Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

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Citations

Apr 12, 2016·Chemico-biological Interactions·C Linn CadieuxDouglas Cerasoli
May 5, 2016·Expert Opinion on Drug Metabolism & Toxicology·Victor A VoicuDalia Simona Miron
Jun 29, 2016·Archives of Toxicology·Franz WorekHorst Thiermann
Dec 15, 2016·Expert Opinion on Therapeutic Patents·Stanton F McHardyMatthew C Valdez
May 16, 2017·Journal of Neurochemistry·Israel Silman, Joel L Sussman
Nov 16, 2017·Expert Opinion on Drug Discovery·Bernhard BiersackRainer Schobert
Nov 18, 2018·Chemistry : a European Journal·Andrew J FranjesevicChristopher M Hadad
Jun 9, 2020·Archives of Toxicology·Franz WorekTimo Wille
Mar 18, 2020·Biomolecules·Alexandre A de CastroTeodorico C Ramalho
Apr 4, 2018·Toxicology Letters·Francine S KatzMilan N Stojanovic
Nov 6, 2018·Chemico-biological Interactions·Shengzhuang TangSeok Ki Choi
Jan 8, 2021·Arhiv za higijenu rada i toksikologiju·Nikolina Maček Hrvat, Zrinka Kovarik

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