4-bromo-2-(3-fluoropyridin-2-yl)-6-nitrophenylamine | 1052686-58-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-bromo-2-(3-fluoropyridin-2-yl)-6-nitrophenylamine
• 英文别名: 4-Bromo-2-(3-fluoropyridin-2-yl)-6-nitroaniline；4-bromo-2-(3-fluoropyridin-2-yl)-6-nitroaniline
• CAS: 1052686-58-4
• 化学式: C₁₁H₇BrFN₃O₂
• 分子量: 312.098
• InChiKey: WBIYOMBWUKJHJQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  84.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-bromo-2-(3-fluoropyridin-2-yl)-6-nitrophenylamine 在 四(三苯基膦)钯 、 potassium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 3-(4-amino-3-(3-fluoropyridin-2-yl)-5-nitrophenyl)pyridine 1-oxide
  参考文献：
  名称：

  Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy

  摘要：

  A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.022
• 作为产物：
  描述：

  2-氯-3-氟吡啶 在 四(三苯基膦)钯 、 溴 、 sodium acetate 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 水 、 溶剂黄146 为溶剂， 生成 4-bromo-2-(3-fluoropyridin-2-yl)-6-nitrophenylamine
  参考文献：
  名称：

  Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy

  摘要：

  A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.022

文献信息

• Novel Dual-Targeting Benzimidazole Urea Inhibitors of DNA Gyrase and Topoisomerase IV Possessing Potent Antibacterial Activity: Intelligent Design and Evolution through the Judicious Use of Structure-Guided Design and Stucture−Activity Relationships
  作者：Paul S. Charifson、Anne-Laure Grillot、Trudy H. Grossman、Jonathan D. Parsons、Michael Badia、Steve Bellon、David D. Deininger、Joseph E. Drumm、Christian H. Gross、Arnaud LeTiran、Yusheng Liao、Nagraj Mani、David P. Nicolau、Emanuele Perola、Steven Ronkin、Dean Shannon、Lora L. Swenson、Qing Tang、Pamela R. Tessier、Ski-Kai Tian、Martin Trudeau、Tiansheng Wang、Yunyi Wei、Hong Zhang、Dean Stamos

  DOI：10.1021/jm800318d

  日期：2008.9.11

  hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.

  为了克服影响所有目前使用的抗生素种类的细菌耐药性问题，发现具有新颖作用机制的新型抗菌剂是必要的。细菌DNA促旋酶和拓扑异构酶IV是氟喹诺酮类抗生素的特征明确的临床验证靶标，它们通过抑制催化亚基发挥其抗菌活性。通过与它们的ATP位点相互作用来抑制这些靶标在临床上不太成功。提出了一种新型的低分子量，与ATP位点结合的回旋酶和拓扑异构酶IV合成抑制剂的发现和表征。苯并咪唑脲是两种酶的双重靶向抑制剂，并且对引起医院和社区获得性感染的各种相关病原体具有有效的抗菌活性。描述了通过使用结构指导的设计，建模和结构-活性关系来发现和优化这种新型抗菌剂。提供了在两种啮齿动物感染模型中通过口服和静脉内给药的酶抑制，抗菌活性和体内功效的数据。
• Gyrase inhibitors and uses thereof
  申请人：Charifson Paul

  公开号：US20130030004A1

  公开（公告）日：2013-01-31

  The present invention relates to compounds of formula I: or a pharmaceutically acceptable salt thereof, that inhibit bacterial gyrase and/or TopoIV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordingly, the present invention also relates to methods for treating bacterial infections in mammals.

  本发明涉及公式I的化合物：或其药学上可接受的盐，其抑制细菌陀螺酶和/或TopoIV，以及包含该化合物的药学上可接受的组合物。这些化合物及其组合物在治疗细菌感染方面很有用。因此，本发明还涉及用于治疗哺乳动物细菌感染的方法。
• US8394803B2
  申请人：——

  公开号：US8394803B2

  公开（公告）日：2013-03-12
• [EN] BENZIMIDAZOLE DERIVATIVES AS GYRASE INHIBITORS<br/>[FR] DERIVES DE BENZIMIDAZOLE UTILISES EN TANT QU'INHIBITEURS DE LA GYRASE
  申请人：VERTEX PHARMA

  公开号：WO2007056330A1

  公开（公告）日：2007-05-18

  [EN] The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt thereof, that inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordingly, the present invention also relates to methods for treating bacterial infections in mammals.
  [FR] La présente invention concerne des composés de formule (I) : ou un sel acceptable du point de vue pharmaceutique de ceux-ci, qui inhibent la gyrase bactérienne et/ou la topoisomérase IV bactérienne ; et des compositions acceptables du point de vue pharmaceutique comprenant lesdits composés. Ces composés, et les compositions de ceux-ci, sont utiles dans le traitement d'une infection bactérienne. Par conséquent, la présente invention concerne également des procédés servant à traiter des infections bactériennes chez des mammifères.
• Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy
  作者：Emanuele Perola、Dean Stamos、Anne-Laure Grillot、Steven Ronkin、Tiansheng Wang、Arnaud LeTiran、Qing Tang、David D. Deininger、Yusheng Liao、Shi-Kai Tian、Joseph E. Drumm、David P. Nicolau、Pamela R. Tessier、Nagraj Mani、Trudy H. Grossman、Paul S. Charifson

  DOI：10.1016/j.bmcl.2014.03.022

  日期：2014.5

  A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models. (C) 2014 Elsevier Ltd. All rights reserved.