Design of a Potent Reactivator of Tabun-Inhibited AcetylcholinesteraseSynthesis and Evaluation of (<i>E</i>)-1-(4-Carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene Dibromide (K203)

Musílek, Kamil; Jun, Daniel; Cabal, Jiřı́; Kassa, Jiřı́; Gunn‐Moore, Frank; Kuča, Kamil

doi:10.1021/jm070653r

Cited by 99 publications

(94 citation statements)

References 35 publications

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“…Therefore, the second oxime, involved into the combination, should be the oxime sufficiently effective against tabun. For our experiments, trimedoxime or the oxime K203 was chosen because trimedoxime has at least some effect against tabun-inhibited AChE (13) and the oxime K203 was found to be a promising oxime against tabun (11,19,30).…”

Section: Discussionmentioning

confidence: 99%

“…Although some of them can be considered to be promising oximes against some nerve agents, none of them is sufficiently effective against all nerve agents regardless of their chemical structure (28,32). Recently, the oxime K203 [1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide] was synthesized at our Department of Toxicology (30) and its pharmacokinetics was studied (7). Based on in vitro and in vivo evaluation of its reactivating, therapeutic and neuroprotective efficacy, it was considered to be the promising oxime against tabun but not against cyclosarin and soman (11,12,14,15,16,19).…”

Section: Introductionmentioning

confidence: 99%

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A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

Kassa¹,

Karasová²

2011

Mil. Med. Sci. Lett.

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SummaryThe ability of three oximes (HI-6, trimedoxime, K203) to reduce cyclosarin-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) using a functional observational battery. Cyclosarin-induced neurotoxicity and the neuroprotective effects of HI-6, trimedoxime or K203 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with cyclosarin at a sublethal dose (80 µg/kg i.m.; 70% of LD 50 value) were monitored by the functional observational battery at 24 hours and 7 days following cyclosarin challenge. The results indicate that all types of antidotal treatment are able to survive cyclosarin-poisoned rats 7 days following cyclosarin poisoning while one non-treated cyclosarin-poisoned rats died within 24 hours following cyclosarin challenge. All three oximes alone as well as both oxime mixtures combined with atropine were able to slightly decrease cyclosarin-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all cyclosarin-induced acute neurotoxic signs and symptoms. Their ability to reduce cyclosarininduced acute neurotoxicity was almost the same regardless of type of antidotal treatment. Thus, the tested combinations of oximes were not able to increase the neuroprotective effectiveness of antidotal treatment of acute cyclosarin poisoning compared to the individual oximes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

Kassa¹,

Karasová²

2011

Mil. Med. Sci. Lett.

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“…Since all these drawbacks have not been fully addressed so far, we still have to rely on the pyridiniumbased AChE reactivators. A few decades ago, these charged reactivators have been developed and since then only a few more with an interesting profile and concomitantly overwhelming the capability of currently used oximes have been introduced (K027 or K203) 31 . In this regard, particular attention is paid to Hlö-7 being considered one of the most potent bis-pyridinium reactivator with broad profile.…”

Section: Reactivation Of Achementioning

confidence: 99%

HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION

Psotka¹,

Maliňák²,

Górecki³

et al. 2017

Mil. Med. Sci. Lett.

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SummaryThe treatment of organophosphate (OP) poisoning consists of the administration of a parasympatholytic agent, an anticonvulsant and an acetylcholinesterase (AChE) reactivator. Since there is no broad AChE reactivator available, a post-treatment strategy currently exploits administration of different types of oximes depending on the exposure of OP. In this contribution, we summarize all the available data about AChE reactivator HLö-7 including its synthesis, physico-chemical properties, pharmacokinetic and pharmacodynamics profile, and its efficacy in vitro and in vitro.

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“…150 Many new oximes have been synthesized, and their capacities of AChE reactivation evaluated. [157][158][159][160][161][162][163][164][165][166][167][168][169][170] Figure 15 shows the structure of some of those new promising bis-pyridinium oximes. For example 1,7-heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, which is 200 times more active than 2-PAM and could lead to the development of compounds able to reactivate aged phosphorylated HuAChE.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

“…158 Other examples of new promising bis-pyridinium oximes are K027 [1-(4-hydroxyiminomethylpyridinium)- 3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], which display low toxicity against different types of human cells but have a very good capacity to reactivate HuAChE inhibited with tabun, 161,165 and similar oximes with an unsaturated liker, like K203 ((E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide). 166,167 There are evidences that at least some oximes (mainly HI-6 and HLö-7) also act on the treatment of intoxications through direct pharmacological effects, which are not related to AChE reactivation. However, the mechanism of these effects is not well understood yet, but there are some hypotheses.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

228

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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Design of a Potent Reactivator of Tabun-Inhibited AcetylcholinesteraseSynthesis and Evaluation of (E)-1-(4-Carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene Dibromide (K203)

Cited by 99 publications

References 35 publications

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION

Organophosphorus compounds as chemical warfare agents: a review

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