methyl 5-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)pentanoate | 1233220-94-4

• 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: methyl 5-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)pentanoate
• 英文别名: Methyl5-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)pentanoate；methyl 5-[5-[(2,4-diaminoquinazolin-6-yl)methylamino]-2-methoxyphenoxy]pentanoate
• CAS: 1233220-94-4
• 化学式: C₂₂H₂₇N₅O₄
• 分子量: 425.487
• InChiKey: YRXPCPGTMSVNEK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  碳酸胍 、 methyl 5-[5-(3-cyano-4-fluorobenzylamino)-2-methoxyphenoxy]pentanoate 以 N,N-二甲基乙酰胺 为溶剂， 反应 5.0h， 以48%的产率得到methyl 5-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)pentanoate
  参考文献：
  名称：

  Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

  摘要：

  Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme: cofactor: inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4- diaminoquinazoline scaffold. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.04.020

文献信息

• Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase
  作者：Norbert Schormann、Sadanandan E. Velu、Srinivasan Murugesan、Olga Senkovich、Kiera Walker、Bala C. Chenna、Bidhan Shinkre、Amar Desai、Debasish Chattopadhyay

  DOI：10.1016/j.bmc.2010.04.020

  日期：2010.6.1

  Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme: cofactor: inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4- diaminoquinazoline scaffold. (C) 2010 Elsevier Ltd. All rights reserved.