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48. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning

Author

Masson P. and Nachon F.

Subjects
Organophosphate poisoning, Oxime, Post-exposure treatment, Prophylaxis, Bioscavenger, Acetylcholinesterase, Nerve agent
Abstract

© 2017 International Society for Neurochemistry.Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre- and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

Published
2017

49. Application of the Ugi Multicomponent Reaction in the Synthesis of Reactivators of Nerve Agent Inhibited Acetylcholinesterase

Author

Koning, M.C. de, Joosen, M.J.A., Worek, F., Nachon, F., Grol, M. van, Klaassen, S.D., Alkema, D.P.W., Wille, T., and Bruijn, H.M. de

Subjects
TS - Technical Sciences, Unclassified drug, Defence Research, CBRN - CBRN Protection, Defence, Safety and Security, Cholinesterase inhibitor, Observation, Weapon & Protection Systems, Chemistry, Pralidoxime, Safety and Security, Oxime derivative, Acetylcholinesterase, Safety, 2015 Observation, Weapon & Protection Systems, Imidazole, Imidazole derivative, Nerve gas
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

Published
2017

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