Issue 22, 2016

Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase

Abstract

Poisoning by organophosphorus nerve agents and pesticides is a serious public and military health issue with over 200 000 fatalities annually worldwide. Conventional emergency treatment consists of rapid administration of atropine and pyridinium oxime as an antidote. The reactivation of acetylcholinesterase (AChE) in the central nervous system (CNS) by the oxime is inefficient due to the fact that positively charged pyridiniums do not readily cross the blood brain barrier (BBB). Herein, we described the synthesis and in vitro evaluation of four donepezil-based non quaternary reactivators. The compounds 1–4 have been prepared in 7–8 linear steps in 1–9% overall yields and oximes 1–3 show better ability (8 fold higher) than pralidoxime to reactivate VX-inhibited human AChE (VX-hAChE). Besides, oxime 2 is 5 to 11 fold more efficient than pralidoxime and HI-6 respectively for the reactivation of VX-inhibited human butyrylcholinesterase (VX-hBChE).

Graphical abstract: Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase

Supplementary files

Article information

Article type
Paper
Submitted
30 Nov 2015
Accepted
03 Feb 2016
First published
03 Feb 2016

RSC Adv., 2016,6, 17929-17940

Author version available

Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase

J. Renou, J. Dias, G. Mercey, T. Verdelet, C. Rousseau, A. Gastellier, M. Arboléas, M. Touvrey-Loiodice, R. Baati, L. Jean, F. Nachon and P. Renard, RSC Adv., 2016, 6, 17929 DOI: 10.1039/C5RA25477A

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