(E)-1-(4-bromobut-2-enyl)-4-hydroxyiminomethylpyridinium bromide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (E)-1-(4-bromobut-2-enyl)-4-hydroxyiminomethylpyridinium bromide
• 英文别名: (NE)-N-[[1-[(E)-4-bromobut-2-enyl]pyridin-1-ium-4-yl]methylidene]hydroxylamine;bromide
• 化学式: Br*C₁₀H₁₂BrN₂O
• 分子量: 336.026
• InChiKey: XUPQHTHPWNNNCW-TYYBGVCCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.26
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  36.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-1-(4-bromobut-2-enyl)-4-hydroxyiminomethylpyridinium bromide 、 4-吡啶甲酰胺 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以82%的产率得到(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide
  参考文献：
  名称：

  Oxime K203: a drug candidate for the treatment of tabun intoxication

  摘要：

  For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.

  DOI：

  10.1007/s00204-018-2377-7
• 作为产物：
  描述：

  4-吡啶甲醛肟 、 1,4-二溴-2-丁烯 以 丙酮 为溶剂， 反应 2.0h， 以95%的产率得到(E)-1-(4-bromobut-2-enyl)-4-hydroxyiminomethylpyridinium bromide
  参考文献：
  名称：

  Two Step Synthesis of a Non-symmetric Acetylcholinesterase Reactivator

  摘要：

  我们采用两种不同的方法，通过适当的(E)-1-(4-溴丁-2-烯基)-2-或 4-羟基亚氨基甲基吡啶鎓溴化物进行两步合成，制备出了新开发的极具前景的乙酰胆碱酯酶反应活化剂(E)-1-(2-羟基亚氨基甲基吡啶鎓)-4-(4-羟基亚氨基甲基吡啶鎓)-丁-2-烯二溴化物。随后，比较了两种方法制备的所需产物的纯度和产量。最后，对其重新激活几种神经抑制剂乙酰胆碱酯酶的效力进行了测试。

  DOI：

  10.3390/12081755

文献信息

• Fluorinated pyridinium oximes as potential reactivators for acetylcholinesterases inhibited by paraoxon organophosphorus agent
  作者：Hee Chun Jeong、No-Joong Park、Chong Hak Chae、Kamil Musilek、Jiri Kassa、Kamil Kuca、Young-Sik Jung

  DOI：10.1016/j.bmc.2009.07.043

  日期：2009.9

  fluorinated oxime compounds was designed and synthesized in order to probe the effect of fluorine substitution on reactivation of inhibited acetylcholinesterase (AChE) by organophosphorus agents. Permeability measurements, using the Parallel Artificial Membrane Permeation Assays (PAMPA) method, were employed to experimentally demonstrate that membrane permeabilities of the series of oximes increase in

  设计并合成了一系列氟化肟化合物，以探讨氟取代对有机磷试剂对受抑制的乙酰胆碱酯酶（AChE）的再活化的影响。使用平行人工膜渗透测定法（PAMPA）进行的渗透率测量用于实验证明一系列肟的膜渗透率与氟原子数的增加成比例地增加。在这项研究中探索的化合物中，单氟氨基甲酰基醛肟4b是对氧磷抑制的红细胞（RBC）AChE最有效的活化剂。
• Charged pyridinium oximes with thiocarboxamide moiety are equally or less effective reactivators of organophosphate-inhibited cholinesterases compared to analogous carboxamides
  作者：Zuzana Kohoutova、David Malinak、Rudolf Andrys、Jana Svobodova、Miroslav Psotka、Monika Schmidt、Lukas Prchal、Kamil Musilek

  DOI：10.1080/14756366.2022.2041628

  日期：2022.12.31

  Abstract The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found

  摘要 有机磷解毒剂，即所谓的肟，能够通过从磷酸化酶的活性位点切割有机磷酸盐来恢复乙酰胆碱酯酶 (AChE) 或丁酰胆碱酯酶 (BChE) 的酶促功能。在这项工作中，设计、制备和测试了含有硫代甲酰胺部分的带电吡啶鎓肟。它们的稳定性和 p K a发现其性质类似于母体羧酰胺（K027、K048 和 K203）。在低 µM 水平的 AChE 和高 µM 水平的 BChE 中发现硫代羧酰胺的抑制能力。在神经毒剂替代物和对氧磷抑制的人重组 AChE 和 BChE 上筛选它们的再激活特性。一种硫代甲酰胺能够有效地恢复 NEMP-和 NEDPA-AChE 的功能，而两种硫代甲酰胺能够重新激活被所有测试的有机磷酸盐抑制的 BChE。这些结果通过再活化动力学得到证实，其中硫代甲酰胺被证明是有效的，但与甲酰胺相比，再活化剂的效力较低。
• 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)
  作者：Kamil Musilek、Daniel Jun、Jiri Cabal、Jiri Kassa、Frank Gunn-Moore、Kamil Kuca

  DOI：10.1021/jm070653r

  日期：2007.11.1

  Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Among the organophosphates, with the exception of soman, tabun (GA) intoxications are the least responsive to treatment with commercially available therapeutics. A rational design was used to increase reactivation ability and decrease the toxicity of the novel reactivator. (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203) has better properties than previously tested compounds in vitro and, therefore, is a potential candidate for the treatment of GA intoxication in vivo.
• Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase
  作者：Kamil Musilek、Kamil Kuca、Daniel Jun、Vlastimil Dohnal、Martin Dolezal

  DOI：10.1016/j.bmcl.2005.10.059

  日期：2006.2

  Six potential AChE reactivators were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. According to the results, (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as constitution of the linking chain between both pyridinium rings, position of the oxime moiety at the pyridinium ring and presence of quaternary nitrogens. (c) 2005 Elsevier Ltd. All rights reserved.