1-(prop-2-yn-1-yl)imidazole-2-carbaldehyde oxime | 1313032-27-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(prop-2-yn-1-yl)imidazole-2-carbaldehyde oxime
• 英文别名: 1-(3-prop-2-yn-1-yl)imidazole-2-carbaldehyde oxime；1-(prop-2-yn-1-yl)-1H-imidazole-2-carbaldehyde oxime
• CAS: 1313032-27-7
• 化学式: C₇H₇N₃O
• 分子量: 149.152
• InChiKey: PKYYLLPYZNMXIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.32
• 重原子数：
  11.0
• 可旋转键数：
  2.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  50.41
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  1-(prop-2-yn-1-yl)imidazole-2-carbaldehyde oxime 、 N-(3-azidopropyl)-2-(hydroxyimino) acetamide 在 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 叔丁醇 为溶剂， 生成 RS48B
  参考文献：
  名称：

  New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

  摘要：

  We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2-hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mM compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/K-ox) and maximum reactivation rate (k(2)), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.

  DOI：

  10.1074/jbc.m111.230656
• 作为产物：
  描述：

  1-(prop-2-yn-1-yl)imidazole-2-carbaldehyde 在 盐酸羟胺 、 sodium carbonate 作用下， 以 水 为溶剂， 反应 1.0h， 以78%的产率得到1-(prop-2-yn-1-yl)imidazole-2-carbaldehyde oxime
  参考文献：
  名称：

  [EN] CATALYTIC SCAVENGERS OF ORGANOPHOSPHATES TO POTENTIATE BUTYRYLCHOLINESTERASE (BCHE) AS A CATALYTIC BIOSCAVENGER AND METHODS FOR MAKING AND USING THEM
  [FR] PIÉGEURS CATALYTIQUES D'ORGANOPHOSPHATES POUR POTENTIALISER LA BUTYRYLCHOLINESTÉRASE (HBCHE)

  摘要：

  提供了N-烷基咪唑-2-醛肟，包括阳离子咪唑盐和不带电的三级咪唑醛肟，以及制备和使用它们的组合物和方法，包括重新激活被有机磷酸酯（OP）抑制的人丁酰胆碱酯酶（hBChE）或乙酰胆碱酯酶（hAChE）的方法。通过给予本发明的组合物，不活性或结合的hBChE-OP或hAChE-OP被重新激活，完成了OP的催化周转和失活循环；在替代实施方案中，可逆保护hBChE和hAChE免受OP不可逆失活的次要机制以及再激活组织AChE也有助于整体功效。

  公开号：

  WO2015057822A1

文献信息

• Imidazole Aldoximes Effective in Assisting Butyrylcholinesterase Catalysis of Organophosphate Detoxification
  作者：Rakesh K. Sit、Valery V. Fokin、Gabriel Amitai、K. Barry Sharpless、Palmer Taylor、Zoran Radić

  DOI：10.1021/jm401650z

  日期：2014.2.27

  Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate.
• Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases
  作者：Nikola Maraković、Anamarija Knežević、Vladimir Vinković、Zrinka Kovarik、Goran Šinko

  DOI：10.1016/j.cbi.2016.05.035

  日期：2016.11

  Within this study, we designed and synthesized four new oxime compounds of the N-substituted 2-hydroxyiminoacetamide structure and evaluated their interactions with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our aim was to explore the possibility of extending the dual-binding mode of interaction between the enzyme and the inhibitor to a so-called triple-binding mode of interaction through the introduction of an additional binding moiety. N-substituted 2-hydroxyiminoacetamide 1 was prepared via BOP catalyzed amidation of hydroxyiminoacetic acid with 3-azido-1-phenylpropylamine. An azide group enabled us to prepare more elaborate structures 2-4 by the copper-catalyzed azide-alkyne cycloaddition. The new compounds 1-4 differed in their presumed AChE peripheral site binding moiety, which ranged from an azide group to functionalized heterocycles. Molecular docking studies revealed that all three binding moieties are involved in the non-covalent interactions with ChEs for all of the four compounds, albeit not always in the complete accordance with the proposed hypothesis. All of the four compounds reversibly inhibited the ChEs with their inhibition potency increasing in the same order for both enzymes (1 < 2 < 4 < 3). A higher preference for binding to BChE (K-I from 0.30 mu mol/L to 130 mu mol/L) over AChE (K-I from 50 mmol/L to 1200 mmol/L) was observed for all of the compounds. Compounds were screened for reactivation of cyclosarin-, sarin-and VX-inhibited AChE and BChE. (C) 2016 Elsevier Ireland Ltd. All rights reserved.