2-amino-5-(1-naphthylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one | 1469886-65-4

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-amino-5-(1-naphthylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one
• 英文别名: 2-Amino-5-(1-Naphthylsulfanyl)-3,9-Dihydro-4h-Pyrimido[4,5-B]indol-4-One；2-amino-5-naphthalen-1-ylsulfanyl-3,9-dihydropyrimido[4,5-b]indol-4-one
• CAS: 1469886-65-4
• 化学式: C₂₀H₁₄N₄OS
• 分子量: 358.423
• InChiKey: NSASWBYEPOLHJW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1-奈硫酚 、 2-amino-5-chloro-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one 在 copper(l) iodide 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 200.0 ℃ 、2.0 MPa 条件下， 反应 0.5h， 以28%的产率得到2-amino-5-(1-naphthylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one
  参考文献：
  名称：

  Discovery of Potent and Selective Inhibitors of Toxoplasma gondii Thymidylate Synthase for Opportunistic Infections

  摘要：

  Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in iimnunocompromised patients such as organ transplant, cancer, and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species, and specificity is significantly more challenging. We discovered novel substituted-9H-pyrimido[4,5-b]indoles 1-3 with single-digit nanomolar K-i for tgTS, two of which, 2 and 3, are 28- and 122 fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data These results show, for the very first time, that, in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.

  DOI：

  10.1021/ml400208v

文献信息

• Discovery of Potent and Selective Inhibitors of <i>Toxoplasma gondii</i> Thymidylate Synthase for Opportunistic Infections
  作者：Nilesh Zaware、Hitesh Sharma、Jie Yang、Ravi Kumar Vyas Devambatla、Sherry F. Queener、Karen S. Anderson、Aleem Gangjee

  DOI：10.1021/ml400208v

  日期：2013.12.12

  Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in iimnunocompromised patients such as organ transplant, cancer, and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species, and specificity is significantly more challenging. We discovered novel substituted-9H-pyrimido[4,5-b]indoles 1-3 with single-digit nanomolar K-i for tgTS, two of which, 2 and 3, are 28- and 122 fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data These results show, for the very first time, that, in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.