6-(((3S,4R)-3-fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one | 1610628-66-4

• 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: 6-(((3S,4R)-3-fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one
• 英文别名: 6-[[[(3S,4R)-3-fluoro-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1-yl)ethyl]piperidin-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one
• CAS: 1610628-66-4
• 化学式: C₂₃H₂₄F₂N₆O₃
• 分子量: 470.479
• InChiKey: ALQSLGJWIKQNFA-DLBZAZTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  99.7
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  6-(((3S,4R)-3-fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one 、 异噁唑-3-酮 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 0.5h， 生成 6-(((3S,4R)-3-fluoro-1-(2-(7-(isoxazol-3-yloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  参考文献：
  名称：

  Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

  摘要：

  Structure activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 mu M) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.

  DOI：

  10.1021/ml500531p
• 作为产物：
  描述：

  7-fluoro-1-(2-hydroxyethyl)-1,5-naphthyridin-2(1H)-one 在 sodium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 6-(((3S,4R)-3-fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-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

• Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding
  作者：Shahul Hameed P、Praveena Manjrekar、Anandkumar Raichurkar、Vikas Shinde、Jayashree Puttur、Gajanan Shanbhag、Murugan Chinnapattu、Vikas Patil、Suresh Rudrapatana、Sreevalli Sharma、C. N. Naveen Kumar、Radha Nandishaiah、Prashanti Madhavapeddi、D. Sriram、Suresh Solapure、Vasan K. Sambandamurthy

  DOI：10.1021/ml500531p

  日期：2015.7.9

  Structure activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 mu M) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.
• 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。