3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)benzonitrile

• 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-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)benzonitrile
• 英文别名: 3-[4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]quinazolin-2-yl]benzonitrile；3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]benzonitrile
• 化学式: C₂₁H₁₆N₆
• 分子量: 352.398
• InChiKey: BKVJIBAADPVALB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  90.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine 、 3-氰基苯硼酸频哪醇酯 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 三环己基膦 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 14.0h， 以17%的产率得到3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)benzonitrile
  参考文献：
  名称：

  Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions

  摘要：

  Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (K-i approximate to 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 mu M (1-2 mu g/mL) against the H37Ra isolate of M. tuberculosis.

  DOI：

  10.1021/acsmedchemlett.7b00239

文献信息

• Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions
  作者：Tiansheng Wang、Guy Bemis、Brian Hanzelka、Harmon Zuccola、Michael Wynn、Cameron Stuver Moody、Jeremy Green、Christopher Locher、Aixiang Liu、Hongwu Gao、Yuzhou Xu、Shaohui Wang、Jie Wang、Youssef L. Bennani、John A. Thomson、Ute Müh

  DOI：10.1021/acsmedchemlett.7b00239

  日期：2017.12.14

  Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (K-i approximate to 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 mu M (1-2 mu g/mL) against the H37Ra isolate of M. tuberculosis.