N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxamide | 1365252-72-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxamide
• 英文别名: GHQ168；N-benzyl-1-butyl-6-fluoro-7-morpholin-4-yl-4-oxoquinoline-3-carboxamide
• CAS: 1365252-72-7
• 化学式: C₂₅H₂₈FN₃O₃
• 分子量: 437.514
• InChiKey: GOWJFAFHYRTMQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  61.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxamide 在 三氯氧磷 、 氯化铵 、 N,N-二异丙基乙胺 、 盐酸 作用下， 以 乙腈 、 四氢呋喃 、 异丙醇 为溶剂， 反应 27.0h， 以26%的产率得到N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboximidamide hydrochloride
  参考文献：
  名称：

  喹诺酮酰胺为具有体内活性的抗胰头体前导化合物。

  摘要：

  人类非洲锥虫病（HAT）是一种主要的热带疾病，几乎没有可用于治疗的药物，从而推动了对新型活性化合物的需求。最近，氟喹诺酮类抗生素的吗啉代取代的苄基酰胺被确定为对布鲁氏锥虫具有高活性的化合物。由于先导化合物GHQ168在先前的试验中受到水溶性差的挑战，因此本研究的目的是引入结构变异性GHQ168以及配制GHQ168的最终目的是增加其水溶性，同时保持其体外抗锥虫活性。喷雾干燥的GHQ168以及新合成的化合物GHQ242和GHQ243在小鼠体内的药代动力学参数的特征是消除半衰期为1.5到3。腹膜内给药5小时后（4只小鼠/化合物），人血清白蛋白对GHQ168（80％）和GHQ243（45％）的结合具有中等至强的结合力，而GHQ242对人血清白蛋白的结合非常高（＞ 99％）。对于铅化合物GHQ168，表观清除率为112 ml / h，表观分布体积为14升/ kg体重（BW）。感染了T的小鼠。b。在严

  DOI：

  10.1128/aac.01757-15
• 作为产物：
  描述：

  1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 在 N-甲基吗啉 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxamide
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationships of New Quinolone-Type Molecules against Trypanosoma brucei

  摘要：

  Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei, Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC50 = 47 nM) and T. b. rhodesiense (IC50 = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.

  DOI：

  10.1021/jm101439s

文献信息

• Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness
  作者：Michael Berninger、Christine Erk、Antje Fuß、Joseph Skaf、Ehab Al-Momani、Ina Israel、Martina Raschig、Paul Güntzel、Samuel Samnick、Ulrike Holzgrabe

  DOI：10.1016/j.ejmech.2018.04.055

  日期：2018.5

  Human African Trypanosomiasis, also known as African sleeping sickness, is caused by the parasitic protozoa of the genus Trypanosoma. If there is no pharmacological intervention, the parasites can cross the blood-brain barrier (BBB), inevitably leading to death of the patients. Previous investigation identified the quinolone amide GHQ168 as a promising lead compound having a nanomolar activity against

  人类非洲锥虫病，也称为非洲昏睡病，是由锥虫属的寄生原生动物引起的。如果没有药理学干预，这些寄生虫会穿过血脑屏障（BBB），不可避免地导致患者死亡。先前的研究确定喹诺酮酰胺GHQ168是一种有前途的对T. b具有纳摩尔活性的先导化合物。布鲁西。在这里，关于毒性，药代动力学和抗胰锥虫活性，研究了氟取代在不同位置的作用。这种“氟走”导致了新化合物具有更好的代谢稳定性和对T的一致活性。布鲁西。
• Synthesis and Structure–Activity Relationships of New Quinolone-Type Molecules against Trypanosoma brucei
  作者：Georg Hiltensperger、Nicola G. Jones、Sabine Niedermeier、August Stich、Marcel Kaiser、Jamin Jung、Sebastian Puhl、Alexander Damme、Holger Braunschweig、Lorenz Meinel、Markus Engstler、Ulrike Holzgrabe

  DOI：10.1021/jm101439s

  日期：2012.3.22

  Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei, Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC50 = 47 nM) and T. b. rhodesiense (IC50 = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.
• Quinolone Amides as Antitrypanosomal Lead Compounds with <i>In Vivo</i> Activity
  作者：Georg Hiltensperger、Nina Hecht、Marcel Kaiser、Jens-Christoph Rybak、Alexander Hoerst、Nicole Dannenbauer、Klaus Müller-Buschbaum、Heike Bruhn、Harald Esch、Leane Lehmann、Lorenz Meinel、Ulrike Holzgrabe

  DOI：10.1128/aac.01757-15

  日期：2016.8

  the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3

  人类非洲锥虫病（HAT）是一种主要的热带疾病，几乎没有可用于治疗的药物，从而推动了对新型活性化合物的需求。最近，氟喹诺酮类抗生素的吗啉代取代的苄基酰胺被确定为对布鲁氏锥虫具有高活性的化合物。由于先导化合物GHQ168在先前的试验中受到水溶性差的挑战，因此本研究的目的是引入结构变异性GHQ168以及配制GHQ168的最终目的是增加其水溶性，同时保持其体外抗锥虫活性。喷雾干燥的GHQ168以及新合成的化合物GHQ242和GHQ243在小鼠体内的药代动力学参数的特征是消除半衰期为1.5到3。腹膜内给药5小时后（4只小鼠/化合物），人血清白蛋白对GHQ168（80％）和GHQ243（45％）的结合具有中等至强的结合力，而GHQ242对人血清白蛋白的结合非常高（＞ 99％）。对于铅化合物GHQ168，表观清除率为112 ml / h，表观分布体积为14升/ kg体重（BW）。感染了T的小鼠。b。在严