Print Email Facebook Twitter Application of the Ugi Multicomponent Reaction in the Synthesis of Reactivators of Nerve Agent Inhibited Acetylcholinesterase 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 SystemsCBRN - CBRN ProtectionTS - Technical SciencesSafety and SecuritySafetyDefence, Safety and SecurityAcetylcholinesteraseCholinesterase inhibitorImidazoleImidazole derivativeNerve gasOxime derivativePralidoximeUnclassified drug To reference this document use: http://resolver.tudelft.nl/uuid:19e1c5cf-9da1-4881-8ca2-cbcd58d9bd3f 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 Files To receive the publication files, please send an e-mail request to TNO Library.