2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide | 22078-28-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide
• 英文别名: 2-hydroxyimino-N-(2-pyrrolidin-1-ylethyl)acetamide
• CAS: 22078-28-0
• 化学式: C₈H₁₅N₃O₂
• 分子量: 185.226
• InChiKey: STSAGNKPXWLIGB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.34
• 重原子数：
  13.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  64.93
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  1-(2-氨乙基)吡咯烷 、 ethyl 2-(hydroxyimino)acetate 以 乙醇 为溶剂， 以70%的产率得到2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide
  参考文献：
  名称：

  作为有机磷中毒解毒剂的AChE非四价活化剂的体外和计算机评估-是新希望还是盲目的胡同？

  摘要：

  背景技术在过去的十年中，已经引入了潜在的能够穿透CNS的不带电荷的活化剂的概念，作为传统带电荷肟再活化剂的替代方案。然而，该概念带来了几个相关的缺点，例如更高的亲脂性，给药困难，对胆碱酯酶的亲和力较低以及更高的毒性风险。目的在这项研究中，我们比较了从一组五个经典带电活化剂和一组三个最近出版的不带电荷的肟中补充了两个新颖的数据的数据。方法这次，我们仅使用计算机模拟和体外方法。结果我们的数据表明，经测试的不带电荷的肟对胆碱酯酶的亲和力低，不具有高活化活性，并且由于较高的亲脂性而具有更大的毒性风险。我们假设成功治疗OP中毒将需要平衡的理化特性。但是，在这种特殊情况下，满足此类标准并精确定位的计算机（K1280）失败了。结论从给出的数据来看，似乎必须对不带电荷的活化剂的概念进行修改，至少要提高其生物利用度并满足体内给药的要求。

  DOI：

  10.2174/1573406414666180112105657

文献信息

• Dual acting oximes designed for therapeutic decontamination of reactive organophosphates <i>via</i> catalytic inactivation and acetylcholinesterase reactivation
  作者：Jayme Cannon、Shengzhuang Tang、Kelly Yang、Racquel Harrison、Seok Ki Choi

  DOI：10.1039/d1md00194a

  日期：——

  decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of α-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each

  活性有机磷酸盐 (OP) 的治疗性去污的常规方法依赖于肟化合物对 OP 的化学降解。然而，由于它们在乙酰胆碱酯酶 (AChE)（OP 的主要靶标）的再激活中缺乏活性，因此它们的功效受到限制。在这里，我们描述了一组新发现的具有这种双重作用模式的 α-亲核试剂肟衍生物。因此，我们准备了一个 9 成员肟库，每个都由一个 OP 反应性肟核心组成，该核心连接到一个胺端支架，其通过N-烷基官能化。该文库通过对人类和电鳗 OP 灭活的 AChE 亚型进行的酶测定进行筛选，这导致鉴定出与 2-PAM 相当的再激活活性显着增强的三种肟先导。他们能够重新激活被三种 OP 类型（包括对氧磷、毒死蜱和 malaoxon）灭活的两种酶，这表明它们具有广谱的 OP 敏感性。文库中的所有化合物都能够在对氧磷失活中保持催化反应性，在受控条件下，在 pH 值（8.0、10.5）和温度（17、37°C​​）下，相对于二乙酰单肟
• Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure
  作者：Carlos A. Valdez、Doris Lam、Victoria Lao、Alagu Subramanian、Heather A. Enright、Michael A. Malfatti、Nicholas A. Be、Mark L. Dreyer

  DOI：10.1016/j.tet.2023.133598

  日期：2023.9

  An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated

  描述了一种合成肟基肟基肟基化合物的改进方法，该化合物有望作为中枢活性神经毒剂解毒剂。该方法涉及在 HOBT 或 HATU 和二异丙基碳二亚胺存在下将羟基亚氨基乙酸与各种胺偶联。研究发现，优化的方案可以有效地与胺偶联成羟基亚氨基乙酸的活化形式，伯胺的产率在 84% 至 90% 之间，α-取代胺和环胺的产率在 65-75% 之间，同时产生了不错的 41-位阻α,α-取代胺的产率为48%，这是使用先前建立的方法无法获得的。
• New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases
  作者：Rakesh K. Sit、Zoran Radić、Valeria Gerardi、Limin Zhang、Edzna Garcia、Maja Katalinić、Gabriel Amitai、Zrinka Kovarik、Valery V. Fokin、K. Barry Sharpless、Palmer Taylor

  DOI：10.1074/jbc.m111.230656

  日期：2011.6

  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.