(E)-1-(4-bromobut-2-enyl)-4-carbamoylpyridinium 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-carbamoylpyridinium bromide
• 英文别名: 1-[(E)-4-bromobut-2-enyl]pyridin-1-ium-4-carboxamide;bromide
• 化学式: Br*C₁₀H₁₂BrN₂O
• 分子量: 336.026
• InChiKey: ATSNALAEHQIQAS-TYYBGVCCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.97
• 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：
  47
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-吡啶甲醛肟 、 (E)-1-(4-bromobut-2-enyl)-4-carbamoylpyridinium bromide 以 N,N-二甲基甲酰胺 为溶剂， 生成 (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide
  参考文献：
  名称：

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

  摘要：

  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.

  DOI：

  10.1021/jm070653r
• 作为产物：
  描述：

  1,4-二溴-2-丁烯 、 4-吡啶甲酰胺 以 乙腈 为溶剂， 反应 3.0h， 以96%的产率得到(E)-1-(4-bromobut-2-enyl)-4-carbamoylpyridinium bromide
  参考文献：
  名称：

  氟化吡啶鎓肟作为对氧磷有机磷试剂抑制的乙酰胆碱酯酶的潜在活化剂

  摘要：

  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。

  DOI：

  10.1016/j.bmc.2009.07.043

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。
• Pyridinium Oximes with <i>Ortho</i>-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents
  作者：Tamara Zorbaz、David Malinak、Nikola Maraković、Nikolina Maček Hrvat、Antonio Zandona、Michal Novotny、Adam Skarka、Rudolf Andrys、Marketa Benkova、Ondrej Soukup、Maja Katalinić、Kamil Kuca、Zrinka Kovarik、Kamil Musilek

  DOI：10.1021/acs.jmedchem.8b01398

  日期：2018.12.13

  bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the pKa value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the pKa was found to be lower than that of analogous nonchlorinated oximes. All

  合成了六种氯化双吡啶鎓单肟，类似于强效带电活化剂K027，K048和K203，目的是改善亲脂性并降低肟基的p K a值，因此与pH 7.4相比，肟酸的浓度更高非氯化类似物。检查了亲核性，并且p K a被发现低于类似的非氯化肟。所有这些新化合物都能有效地激活被神经毒剂环沙林，沙林和VX抑制的人AChE。最有效的是肟K027的二氯类似物，由于结合亲和力和分子识别能力的提高，具有显着提高的活化共轭酶的能力。沙林，VX和环沙蛋白抑制的AChE的整体重新活化分别比K027高3倍，7倍和8倍。它的通用性，PAMPA渗透性，有利的酸解离常数及其微不足道的细胞毒性作用，以及在全人类血液中成功地离体清除神经毒剂，都需要对该化合物作为有机磷中毒的解毒剂进行进一步分析。
• Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents
  作者：Tamara Zorbaz、David Malinak、Tereza Hofmanova、Nikola Maraković、Suzana Žunec、Nikolina Maček Hrvat、Rudolf Andrys、Miroslav Psotka、Antonio Zandona、Jana Svobodova、Lukas Prchal、Sanja Fingler、Maja Katalinić、Zrinka Kovarik、Kamil Musilek

  DOI：10.1016/j.ejmech.2022.114377

  日期：2022.8

  bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fl

  氟化双吡啶肟的设计和合成旨在提高其亲核性和重新激活磷酸化人重组乙酰胆碱酯酶 (AChE) 和人纯化血浆丁酰胆碱酯酶 (BChE) 与氯化和非卤代肟类似物相关的潜力。与非卤代肟相比，卤代肟表现出较低的 p K a肟基团（氟化 < 氯化 < 非卤化）以及在生理 pH 下形成更高水平的肟阴离子，并且对 AChE 和 BChE 具有更高的结合亲和力。稳定性测试表明，氟化肟在水中是稳定的，而在缓冲环境中，二氟化肟容易快速降解，这反映在它们的再活化能力较低。在沙林、环沙林、VX 和塔崩抑制 AChE 的情况下，单氟肟显示出与非卤代（阿肟除外）和单氯代肟相当的再活化作用，但效率低于二氯代肟。在抑制的 BChE 的再激活中观察到相同的趋势。通过模拟肟与磷酸化 AChE 和 BChE 之间的预活化复合物的广泛分子模型，证实了卤素取代基在将肟稳定在最适合在线亲核攻击的位置方面的优势。卤素取代显示为肟提供额外的
• 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.
• Oxime K203: a drug candidate for the treatment of tabun intoxication
  作者：Lukas Gorecki、Ondrej Soukup、Tomas Kucera、David Malinak、Daniel Jun、Kamil Kuca、Kamil Musilek、Jan Korabecny

  DOI：10.1007/s00204-018-2377-7

  日期：2019.3

  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.