2-(4-benzylpiperazin-1-yl)-N'-(2-(bis(pyridin-2-ylmethyl)amino)acetyl)acetohydrazide | 1449679-58-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2-(4-benzylpiperazin-1-yl)-N'-(2-(bis(pyridin-2-ylmethyl)amino)acetyl)acetohydrazide
• 英文别名: 2-(4-benzylpiperazin-1-yl)-N'-[2-[bis(pyridin-2-ylmethyl)amino]acetyl]acetohydrazide
• CAS: 1449679-58-6
• 化学式: C₂₇H₃₃N₇O₂
• 分子量: 487.605
• InChiKey: UBFPFEYJQOUETN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-苄基-4-(乙氧基羰基甲基)哌嗪 在 N-甲基吗啉 、 1-羟基苯并三唑 、 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 2-(4-benzylpiperazin-1-yl)-N'-(2-(bis(pyridin-2-ylmethyl)amino)acetyl)acetohydrazide
  参考文献：
  名称：

  Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: Comparison with TPEN and PAC-1

  摘要：

  The lipophilic, cell-penetrating zinc chelator N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (K-d), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2'-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN > ZnA-Pyr > ZnA-DPA > PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO4, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO4 reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and RoS production. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.037

文献信息

• [EN] INHIBITORS OF METALLO-BETA-LACTAMASE (MBL) COMPRISING A ZINC CHELATING MOIETY<br/>[FR] INHIBITEURS DE MÉTALLO-BÊTA-LACTAMASE (MBL) COMPRENANT UNE FRACTION DE CHÉLATION DU ZINC
  申请人：UNI I OSLO

  公开号：WO2015049546A1

  公开（公告）日：2015-04-09

  The invention provides compounds according to formula I: A - L - B wherein A represents a lipophilic chelating moiety which is selective for Zn2+ ions; L is a covalent bond or a linker; and B is a vector which is either a moiety capable of interacting with one or more biological structures found in a bacterium (preferably in a bacterial cell wall), for example a penicillin-binding protein such as a metallo-β- lactamase or DD-transferase, or a moiety capable of enhancing transport of the compound across a bacterial cell membrane. Such compounds find use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal. In such a method, the compound of formula I may be administered in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic.

  该发明提供了符合以下公式I的化合物：A - L - B，其中A代表选择性对Zn2+离子的亲脂螯合基团；L是共价键或连接物；B是矢量，可以是能与细菌中的一个或多个生物结构相互作用的基团（最好是在细菌细胞壁中找到的），例如金黄色葡萄球菌结合蛋白（例如金属β-内酰胺酶或DD-转移酶），或者是能增强化合物穿过细菌细胞膜的基团。这种化合物可用于治疗和/或预防人类或非人哺乳动物的细菌感染的方法。在这种方法中，公式I的化合物可以与（同时、分开或顺序地）β-内酰胺类抗生素一起给予。
• Inhibitors of Metallo-Beta-Lactamase (MBL) Comprising a Zinc Chelating Moiety
  申请人：UNIVERSITETET I OSLO

  公开号：US20160244431A1

  公开（公告）日：2016-08-25

  Compounds according to formula I are provided: A-L-B wherein A represents a lipophilic chelating moiety which is selective for Zn 2+ ions; L is a covalent bond or a linker; and B is a vector which is either a moiety capable of interacting with one or more biological structures found in a bacterium (preferably in a bacterial cell wall), for example a penicillin-binding protein such as a metallo-β-lactamase or DD-transferase, or a moiety capable of enhancing transport of the compound across a bacterial cell membrane. A method of treating and/or preventing a bacterial infection in a human or non-human mammal employing such compounds are also provided. In such a method, the compound of formula I may be administered in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic.

  提供符合公式I的化合物：A-L-B，其中A代表亲脂性螯合基团，该基团选择性地与Zn2+离子结合；L是共价键或连接剂；B是载体，可以是与细菌中的一个或多个生物结构相互作用的基团（优选在细菌细胞壁中），例如与金属β-内酰胺酶或DD转移酶等青霉素结合蛋白相互作用的基团，或者是增强化合物穿过细菌细胞膜的基团。还提供了一种使用这些化合物治疗和/或预防人类或非人哺乳动物细菌感染的方法。在这种方法中，公式I的化合物可以与β-内酰胺类抗生素（同时、分别或顺序）联合使用。
• Inhibitors of metallo-beta-lactamase (MBL) comprising a zinc chelating moiety
  申请人：Universitetet I Oslo

  公开号：US10227327B2

  公开（公告）日：2019-03-12

  Compounds according to formula I are provided: A-L-B wherein A represents a lipophilic chelating moiety which is selective for Zn2+ ions; L is a covalent bond or a linker; and B is a vector which is either a moiety capable of interacting with one or more biological structures found in a bacterium (preferably in a bacterial cell wall), for example a penicillin-binding protein such as a metallo-β-lactamase or DD-transferase, or a moiety capable of enhancing transport of the compound across a bacterial cell membrane. A method of treating and/or preventing a bacterial infection in a human or non-human mammal employing such compounds are also provided. In such a method, the compound of formula I may be administered in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic.

  提供了符合式 I 的化合物： A-L-B 其中 A 代表对 Zn2+ 离子具有选择性的亲脂性螯合分子；L 是共价键或连接体；B 是载体，它可以是能够与细菌（最好是细菌细胞壁）中的一种或多种生物结构（例如青霉素结合蛋白，如金属-β-内酰胺酶或 DD-转移酶）相互作用的分子，也可以是能够增强化合物在细菌细胞膜上转运的分子。还提供了一种利用此类化合物治疗和/或预防人类或非人类哺乳动物细菌感染的方法。在这种方法中，式 I 化合物可与β-内酰胺类抗生素（同时、分别或依次）联合给药。
• INHIBITORS OF METALLO-BETA-LACTAMASE (MBL) COMPRISING A ZINC CHELATING MOIETY
  申请人：Universitetet I Oslo

  公开号：EP3052135B1

  公开（公告）日：2018-07-18
• Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: Comparison with TPEN and PAC-1
  作者：O. Alexander H. Åstrand、Gulzeb Aziz、Sidra Farzand Ali、Ragnhild E. Paulsen、Trond Vidar Hansen、Pål Rongved

  DOI：10.1016/j.bmc.2013.06.037

  日期：2013.9

  The lipophilic, cell-penetrating zinc chelator N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (K-d), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2'-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN > ZnA-Pyr > ZnA-DPA > PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO4, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO4 reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and RoS production. (C) 2013 Elsevier Ltd. All rights reserved.