7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one | 1351401-26-7

• 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: 7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one
• 英文别名: 7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2-one
• CAS: 1351401-26-7
• 化学式: C₁₀H₉FN₂O₂
• 分子量: 208.192
• InChiKey: STXFRPCJYGPOQW-UHFFFAOYSA-N

物化性质

• 沸点：
  353.9±42.0 °C(Predicted)
• 密度：
  1.391±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  53.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one 在 potassium carbonate 作用下， 以 吡啶 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate
  参考文献：
  名称：

  Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: Pharmacophore mapping from known antibacterial leads

  摘要：

  Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl) urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 mu M, and not cytotoxic at 50 mu M in eukaryotic cell line. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.08.018
• 作为产物：
  描述：

  2-溴-3-氨基-5-氟吡啶 在 异丙苯 、 三叔丁基膦 、 N-甲基二环己基胺 、 palladium diacetate 、 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 0.17h， 生成 7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one
  参考文献：
  名称：

  具有改善的hERG和抗结核分枝杆菌的体内功效的新型基于N-联氨基氨基哌啶的促旋酶抑制剂

  摘要：

  DNA促旋酶是开发抗结核分枝杆菌药物的临床验证靶标（MTB）。尽管有希望将氟喹诺酮类药物（FQs）用作抗结核药物，但先前对FQs耐药的流行很可能会限制其临床价值。我们描述了一种新型的N-连接的氨基哌啶基烷基喹诺酮类和萘啶酮类，通过抑制DNA促旋酶活性杀死Mtb。DNA促旋酶的抑制机制与氟喹诺酮类截然不同，其抑制氟喹诺酮类抗性Mtb生长的能力证明了这一点。生化研究表明，该类化合物通过单链裂解而不是双链裂解发挥作用，如氟喹诺酮类药物所见。这些化合物对细胞外和细胞内的Mtb具有高度的杀菌作用。铅的优化导致鉴定了具有改善的口服生物利用度并降低了心脏离子通道负担的有效化合物。该系列化合物在各种结核病鼠模型中均有效。

  DOI：

  10.1021/jm500432n

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.
• Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors
  作者：Karyakulam Andrews Bobesh、Janupally Renuka、Rudraraju Reshma Srilakshmi、Swapna Yellanki、Pushkar Kulkarni、Perumal Yogeeswari、Dharmarajan Sriram

  DOI：10.1016/j.bmc.2015.11.039

  日期：2016.1

  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.
• [EN] NOVEL HETEROCYCLIC COMPOUND OR SALT THEREOF<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE INÉDIT OU SON SEL
  申请人：TAISHO PHARMA CO LTD

  公开号：WO2011148962A1

  公开（公告）日：2011-12-01

  　グラム陽性菌、グラム陰性菌及び耐性菌に対して強い抗菌活性を有する薬剤を提供すること。 式［Ｉ］ （式中、Ｘ２とＹ１を結ぶ点線を含む結合は、単結合、又は二重結合を示し、 Ｚ１、Ｚ２、Ｚ３、Ｚ４、Ｚ５、Ｚ６は、窒素原子又は式ＣＨなどを示し、 Ｘ１は、オキソ基で置換されていてもよいＣ１－４アルキレン基を示し、 Ｘ２は結合手又は式ＣＨを示し、 Ｙ１は、式群（ＩＩ）から選ばれるスピロ環基などを示し、 Ｘ３は、Ｃ１－４アルキレン基、式ＮＲ１０（ＣＨ２）ｍ、式ＳＯｎ、又は結合手を示し、 Ｒ７は、Ｃ３－６シクロアルキル基、Ｃ３－６シクロアルケニル基、アリール基、単環複素環基、又は二環複素環基などを示す。）で表される化合物又はその塩は、抗菌剤として有用である。
• Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: Pharmacophore mapping from known antibacterial leads
  作者：Karyakulam Andrews Bobesh、Janupally Renuka、Variam Ullas Jeankumar、Singh Kakan Shruti、Jonnalagadda Padma Sridevi、Perumal Yogeeswari、Dharmarajan Sriram

  DOI：10.1016/j.ejmech.2014.08.018

  日期：2014.10

  Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl) urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 mu M, and not cytotoxic at 50 mu M in eukaryotic cell line. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Novel N-Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against <i>Mycobacterium tuberculosis</i>
  作者：Shahul Hameed P、Vikas Patil、Suresh Solapure、Umender Sharma、Prashanti Madhavapeddi、Anandkumar Raichurkar、Murugan Chinnapattu、Praveena Manjrekar、Gajanan Shanbhag、Jayashree Puttur、Vikas Shinde、Sreenivasaiah Menasinakai、Suresh Rudrapatana、Vijayashree Achar、Disha Awasthy、Radha Nandishaiah、Vaishali Humnabadkar、Anirban Ghosh、Chandan Narayan、V. K. Ramya、Parvinder Kaur、Sreevalli Sharma、Jim Werngren、Sven Hoffner、Vijender Panduga、C. N. Naveen Kumar、Jitendar Reddy、Mahesh Kumar KN、Samit Ganguly、Sowmya Bharath、Ugarkar Bheemarao、Kakoli Mukherjee、Uma Arora、Sheshagiri Gaonkar、Michelle Coulson、David Waterson、Vasan K. Sambandamurthy、Sunita M. de Sousa

  DOI：10.1021/jm500432n

  日期：2014.6.12

  value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage

  DNA促旋酶是开发抗结核分枝杆菌药物的临床验证靶标（MTB）。尽管有希望将氟喹诺酮类药物（FQs）用作抗结核药物，但先前对FQs耐药的流行很可能会限制其临床价值。我们描述了一种新型的N-连接的氨基哌啶基烷基喹诺酮类和萘啶酮类，通过抑制DNA促旋酶活性杀死Mtb。DNA促旋酶的抑制机制与氟喹诺酮类截然不同，其抑制氟喹诺酮类抗性Mtb生长的能力证明了这一点。生化研究表明，该类化合物通过单链裂解而不是双链裂解发挥作用，如氟喹诺酮类药物所见。这些化合物对细胞外和细胞内的Mtb具有高度的杀菌作用。铅的优化导致鉴定了具有改善的口服生物利用度并降低了心脏离子通道负担的有效化合物。该系列化合物在各种结核病鼠模型中均有效。