2-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-6-methyl-1H-benzo[d]imidazole-5-carbonitrile | 1613053-90-9

• 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: 2-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-6-methyl-1H-benzo[d]imidazole-5-carbonitrile
• 英文别名: 2-[1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1-yl)ethyl]piperidin-4-yl]-6-methyl-1H-benzimidazole-5-carbonitrile
• CAS: 1613053-90-9
• 化学式: C₂₄H₂₃FN₆O
• 分子量: 430.485
• InChiKey: UKYXFAICKBWYQW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  88.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-羟基苯磺酰胺 、 2-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-6-methyl-1H-benzo[d]imidazole-5-carbonitrile 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 0.5h， 以29%的产率得到4-(5-(2-(4-(5-cyano-6-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yloxy)benzenesulfonamide
  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：

  4,5-diamino-2-methyl-benzonitrile 在 盐酸 、 sodium carbonate 、 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-6-methyl-1H-benzo[d]imidazole-5-carbonitrile
  参考文献：
  名称：

  Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing

  摘要：

  Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.

  DOI：

  10.1021/ml5001728

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.
• Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing
  作者：Shahul Hameed P、Anandkumar Raichurkar、Prashanti Madhavapeddi、Sreenivasaiah Menasinakai、Sreevalli Sharma、Parvinder Kaur、Radha Nandishaiah、Vijender Panduga、Jitendar Reddy、Vasan K. Sambandamurthy、D. Sriram

  DOI：10.1021/ml5001728

  日期：2014.7.10

  Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.