tert-butyl 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxylate | 1613053-68-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: tert-butyl 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxylate
• CAS: 1613053-68-1
• 化学式: C₂₀H₂₈N₄O₄
• 分子量: 388.467
• InChiKey: MQSJCGJMBURDBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.96
• 重原子数：
  28.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  76.9
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 7-methoxy-1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one
  参考文献：
  名称：

  Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors

  摘要：

  Recently numerous non-fluoroquinolone-based bacterial type II topoisomerase inhibitors from both the GyrA and GyrB classes have been reported as antibacterial agents. Inhibitors of the GyrA class include aminopiperidine-based novel bacterial type II topoisomerase inhibitors (NBTIs). However, inhibition of the cardiac ion channel remains a serious liability for the aminopiperidine based NBTIs. In this paper we replaced central aminopiperidine linker with piperazine moiety and tested for its biological activity. We developed a series of twenty four compounds with a piperazine linker 1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one, by following a multistep protocol. Among them compound 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-nitrophenyl)piperazine-1-carboxamide (11) was the most promising inhibitor with Mycobacterium tuberculosis (MTB) DNA gyrase enzyme supercoiling IC50 of 0.29 +/- 0.22 mu M, with a good MTB MIC of 3.45 mu M. These kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.039
• 作为产物：
  描述：

  7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one 在 吡啶 、 potassium carbonate 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 tert-butyl 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxylate
  参考文献：
  名称：

  Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors

  摘要：

  Recently numerous non-fluoroquinolone-based bacterial type II topoisomerase inhibitors from both the GyrA and GyrB classes have been reported as antibacterial agents. Inhibitors of the GyrA class include aminopiperidine-based novel bacterial type II topoisomerase inhibitors (NBTIs). However, inhibition of the cardiac ion channel remains a serious liability for the aminopiperidine based NBTIs. In this paper we replaced central aminopiperidine linker with piperazine moiety and tested for its biological activity. We developed a series of twenty four compounds with a piperazine linker 1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one, by following a multistep protocol. Among them compound 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-nitrophenyl)piperazine-1-carboxamide (11) was the most promising inhibitor with Mycobacterium tuberculosis (MTB) DNA gyrase enzyme supercoiling IC50 of 0.29 +/- 0.22 mu M, with a good MTB MIC of 3.45 mu M. These kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.039

文献信息

• Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing
  作者：Shahul Hameed P、Anandkumar Raichurkar、Prashanti Madhavapeddi、Sreenivasaiah Menasinakai、Sreevalli Sharma、Parvinder Kaur、Radha Nandishaiah、Vijender Panduga、Jitendar Reddy、Vasan K. Sambandamurthy、D. Sriram

  DOI：10.1021/ml5001728

  日期：2014.7.10

  Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.