3-((2-chloroquinazolin-4-yl)(methyl)amino)propanenitrile

• 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: 3-((2-chloroquinazolin-4-yl)(methyl)amino)propanenitrile
• 英文别名: 3-[(2-Chloroquinazolin-4-yl)-methylamino]propanenitrile
• 化学式: C₁₂H₁₁ClN₄
• 分子量: 246.699
• InChiKey: AALDWESTZAWDHC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  52.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-((2-chloroquinazolin-4-yl)(methyl)amino)propanenitrile 在 palladium 10% on activated carbon 、 甲酸铵 作用下， 以 乙醇 、 1,2-二氯乙烷 、 正丁醇 为溶剂， 反应 2.17h， 生成 3-(methyl(2-(methyl(1-methylpiperidin-4-yl)amino)quinazolin-4-yl)amino)propanenitrile
  参考文献：
  名称：

  Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes

  摘要：

  The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti- leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.

  DOI：

  10.1021/acs.jmedchem.0c00570
• 作为产物：
  描述：

  2,4-二氯喹唑啉 、 3-甲胺基丙腈 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以76%的产率得到3-((2-chloroquinazolin-4-yl)(methyl)amino)propanenitrile
  参考文献：
  名称：

  Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes

  摘要：

  The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti- leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.

  DOI：

  10.1021/acs.jmedchem.0c00570

文献信息

• Novel Thienopyrimidine Inhibitors of <i>Leishmania N</i>-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
  作者：Andrew S. Bell、Zhiyong Yu、Jennie A. Hutton、Megan H. Wright、James A. Brannigan、Daniel Paape、Shirley M. Roberts、Charlotte L. Sutherell、Markus Ritzefeld、Anthony J. Wilkinson、Deborah F. Smith、Robin J. Leatherbarrow、Edward W. Tate

  DOI：10.1021/acs.jmedchem.0c00570

  日期：2020.7.23

  The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti- leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.