(S)-6-((1-(2-(2-oxo-7-(tetrahydrofuran-3-yloxy)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

• 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: (S)-6-((1-(2-(2-oxo-7-(tetrahydrofuran-3-yloxy)-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-[[[1-[2-[2-oxo-7-[(3S)-oxolan-3-yl]oxy-1,5-naphthyridin-1-yl]ethyl]piperidin-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one
• 化学式: C₂₇H₃₂N₆O₅
• 分子量: 520.588
• InChiKey: WAVHAGZFFINPKM-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-((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 、 (S)-3-羟基四氢呋喃 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 0.5h， 生成 (S)-6-((1-(2-(2-oxo-7-(tetrahydrofuran-3-yloxy)-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

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.