(1E)-2-(2',4'-diamino-6'-oxo-1',6'-dihydro-5'-pyrimidinyl)-4-phenylbutanaloxime | 1199509-53-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (1E)-2-(2',4'-diamino-6'-oxo-1',6'-dihydro-5'-pyrimidinyl)-4-phenylbutanaloxime
• 英文别名: 2,4-diamino-5-[(1E)-1-hydroxyimino-4-phenylbutan-2-yl]-1H-pyrimidin-6-one
• CAS: 1199509-53-9
• 化学式: C₁₄H₁₇N₅O₂
• 分子量: 287.321
• InChiKey: MGYHIWPSLFGWIZ-CAOOACKPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,6-diamino-5-(1-nitromethyl)-3-phenylpropyl-3H-pyrimidin-4-one 在 苯硫酚 、 三乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (1Z)-2-(2',4'-diamino-6'-oxo-1',6'-dihydro-5'-pyrimidinyl)-4-phenylbutanaloxime 、 (1E)-2-(2',4'-diamino-6'-oxo-1',6'-dihydro-5'-pyrimidinyl)-4-phenylbutanaloxime
  参考文献：
  名称：

  Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases

  摘要：

  Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

  DOI：

  10.1021/jm901059x

文献信息

• Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases
  作者：Lindsay B. Tulloch、Viviane P. Martini、Jorge Iulek、Judith K. Huggan、Jeong Hwan Lee、Colin L. Gibson、Terry K. Smith、Colin J. Suckling、William N. Hunter

  DOI：10.1021/jm901059x

  日期：2010.1.14

  Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.