Title
Application of the Ugi Multicomponent Reaction in the Synthesis of Reactivators of Nerve Agent Inhibited Acetylcholinesterase
Author
de Koning, M.C.
Joosen, M.J.A.
Worek, F.
Nachon, F.
van Grol, M.
Klaassen, S.D.
Alkema, D.P.W.
Wille, T.
de Bruijn, H.M.
Publication year
2017
Abstract
Recently, a new class of reactivators of chemical warfare agent inhibited acetylcholinesterase (AChE) with promising in vitro potential was developed by the covalent linkage of an oxime nucleophile and a peripheral site ligand. However, the complexity of these molecular structures thwarts their accessibility. We report the compatibility of various oxime-based compounds with the use of the Ugi multicomponent reaction in which four readily accessible building blocks are mixed together to form a product that links a reactivating unit and a potential peripheral site ligand. A small library of imidazole and imidazolium reactivators was successfully synthesized using this method. Some of these compounds showed a promising ability to reactivate AChE inhibited by various types of CWA in vitro. Molecular modeling was used to understand differences in reactivation potential between these compounds. Four compounds were evaluated in vivo using sarin-exposed rats. One of the reactivators showed improved in vivo efficacy compared to the current antidote pralidoxime (2-PAM). © 2017 American Chemical Society. Chemicals/CAS: acetylcholinesterase, 9000-81-1; imidazole, 1467-16-9, 288-32-4; pralidoxime, 6735-59-7
Subject
2015 Observation, Weapon & Protection Systems
CBRN - CBRN Protection
TS - Technical Sciences
Safety and Security
Safety
Defence, Safety and Security
Acetylcholinesterase
Cholinesterase inhibitor
Imidazole
Imidazole derivative
Nerve gas
Oxime derivative
Pralidoxime
Unclassified drug
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DOI
https://doi.org/10.1021/acs.jmedchem.7b01083
TNO identifier
782471
ISSN
0022-2623
Source
Journal of Medicinal Chemistry, 60 (22), 9376-9392
Document type
article