Peripheral site ligand–oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase

Koning, Martijn C. de; Joosen, Marloes J.A.; Noort, Daan; Zuylen, A. van; Tromp, M.C.

doi:10.1016/j.bmc.2010.10.059

Cited by 39 publications

(25 citation statements)

References 34 publications

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“…If the presence of the two positive charges on bispyridinium molecules definitively hampers CNS penetration, increasing the lipophilicity by substituting the peripheral site pyridinium by an uncharged aromatic moiety appears as a valid strategy (de Koning et al . ). Promising in vivo results suggest a good central efficiency for phenoxyalkyl pyridinium aldoximes (Chambers et al .…”

Section: Post‐exposure Treatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

124

105

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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 postexposure 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.

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Section: Post‐exposure Treatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

124

105

View full text Add to dashboard Cite

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“…Thus, many scientific teams are trying to develop reactivators for nerve agent-inhibited AChE and/or OP pesticide poisoning. Recently, both quaternary and non-quaternary AChE reactivators have been considered for possible management of OP intoxication, including tabun exposure [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

et al. 2018

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The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.

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“…Oximes can reactivate nerve‐agent‐inhibited AChE, and inhibit free AChE itself at the same time . Thus, the binding affinity of oximes to free AChE should be tested in the course of their AChE reactivation development.…”

Section: Resultsmentioning

confidence: 99%

Reactivation of Paraoxon‐inhibited Acetylcholinesterase by Monoquaternary Pyridinium Oximes with N‐Alkylbromide Side Chains

Lee

Shin

Han

et al. 2015

Bulletin Korean Chem Soc

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Peripheral site ligand–oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase

Cited by 39 publications

References 34 publications

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

Reactivation of Paraoxon‐inhibited Acetylcholinesterase by Monoquaternary Pyridinium Oximes with N‐Alkylbromide Side Chains

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