2-(3-fluoropyridin-2-yl)-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline | 1052686-59-5

• 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: 2-(3-fluoropyridin-2-yl)-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• 英文别名: 2-(3-Fluoropyridin-2-yl)-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• CAS: 1052686-59-5
• 化学式: C₁₇H₁₉BFN₃O₄
• 分子量: 359.165
• InChiKey: OXPSTMZMFRLMTQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.68
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(3-fluoropyridin-2-yl)-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 在 四(三苯基膦)钯 、 甲烷磺酸 、 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-ethyl-3-[4-(3-fluoropyridin-2-yl)-6-pyridin-2-yl-1H-benzimidazol-2-yl]urea
  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 、 potassium acetate 、 sodium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 水 、 溶剂黄146 为溶剂， 生成 2-(3-fluoropyridin-2-yl)-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
  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。
• Second-Generation Antibacterial Benzimidazole Ureas: Discovery of a Preclinical Candidate with Reduced Metabolic Liability
  作者：Anne-Laure Grillot、Arnaud Le Tiran、Dean Shannon、Elaine Krueger、Yusheng Liao、Hardwin O’Dowd、Qing Tang、Steve Ronkin、Tiansheng Wang、Nathan Waal、Pan Li、David Lauffer、Emmanuelle Sizensky、Jerry Tanoury、Emanuele Perola、Trudy H. Grossman、Tim Doyle、Brian Hanzelka、Steven Jones、Vaishali Dixit、Nigel Ewing、Shengkai Liao、Brian Boucher、Marc Jacobs、Youssef Bennani、Paul S. Charifson

  DOI：10.1021/jm500563g

  日期：2014.11.13

  presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic

  化合物3是一种有效的氨基苯并咪唑脲，具有双重抑制细菌回旋酶（GyrB）和拓扑异构酶IV（ParE）的作用，具有广谱革兰氏阳性抗菌活性，并且在啮齿动物细菌感染模型中证明了其有效性。临床前的体外和体内研究表明，化合物3可能通过反应性代谢产物的形成来共价标记肝蛋白，因此具有潜在的安全性。化合物3中的尿素部分被认为可能是反应性代谢产物形成的潜在原因，但由于理化参数较差，其替代导致抗菌活性和/或口服暴露降低。为了鉴定没有反应性代谢物形成潜能的第二代氨基苯并咪唑尿素，我们实施了代谢转移策略，该策略的重点是通过在分子中的其他位置引入代谢软点，将代谢作用从尿素部分转移出去。通过这种策略鉴定出的氨基苯并咪唑尿素34具有与3相似的抗菌活性，并且没有在体内标记肝蛋白，表明反应性代谢物形成的可能性降低/没有潜力。
• 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.