6-(sec-butoxy)-2-chloropyrimidin-4-amine

• 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: 6-(sec-butoxy)-2-chloropyrimidin-4-amine
• 英文别名: 6-(s-Butoxy)-2-chloropyrimidin-4-amine；6-butan-2-yloxy-2-chloropyrimidin-4-amine
• 化学式: C₈H₁₂ClN₃O
• 分子量: 201.656
• InChiKey: VDEPJRBVCVPNFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  61
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(sec-butoxy)-2-chloropyrimidin-4-amine 在 双氧水 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 异丙醇 为溶剂， 反应 0.08h， 生成 RDS 1256
  参考文献：
  名称：

  以结构为指导的方法来鉴定针对锥虫硫醚代谢的新型抗利什曼病二芳基硫醚化合物。

  摘要：

  利什曼原虫是利什曼病的病原体，利什曼病是一种被忽视的热带病，由三种主要临床形式组成：内脏利什曼病（VL），皮肤利什曼病和粘膜皮肤利什曼病。VL由东非和印度次大陆的利什曼原虫donovani以及欧洲，北非和拉丁美洲的婴儿利什曼原虫引起，估计每年导致60,000人死亡。锥虫烷还原酶（TR）被认为是寻找抗利什曼病新药的最佳靶标之一。该酶是人类宿主中寄生虫生存的基础，因为它可减少利什曼原虫的Tryparedoxin / tryparedoxin过氧化物酶系统使用的分子锥虫硫醇。中和宿主巨噬细胞在感染过程中产生的过氧化氢。最近，我们与二芳基硫醚化合物RDS 777（6-（仲丁氧基）-2-（（（3-氯苯基）硫基）嘧啶-4-胺）配合使用，解决了TR的X射线结构，这损害了寄生虫通过高效抑制TR来防御活性氧。该化合物结合到催化位点，并通过氢键结合更多参与催化的残基，即Glu466'，Cys57和Cys52，从而抑制锥虫硫醚的结合。在RDS

  DOI：

  10.1007/s00726-019-02731-4
• 作为产物：
  描述：

  4-氨基-2,6-二氯嘧啶 、 仲丁醇 在 sodium 作用下， 反应 4.0h， 以50%的产率得到6-(sec-butoxy)-2-chloropyrimidin-4-amine
  参考文献：
  名称：

  Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

  摘要：

  The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl) thio)pyrimidin-4-amine) (IC50 = 29.43 mu M), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (K-i 0.25 +/- 0.18 mu M). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.

  DOI：

  10.1080/14756366.2016.1250755

文献信息

• Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism
  作者：Gianni Colotti、Francesco Saccoliti、Marina Gramiccia、Trentina Di Muccio、Jay Prakash、Sunita Yadav、Vikash Kumar Dubey、Giulio Vistoli、Theo Battista、Stefano Mocci、Annarita Fiorillo、Aasia Bibi、Valentina Noemi Madia、Antonella Messore、Roberta Costi、Roberto Di Santo、Andrea Ilari

  DOI：10.1007/s00726-019-02731-4

  日期：2020.2

  reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize the hydrogen peroxide produced by host macrophages during infection. Recently, we solved the X-ray structure of TR in complex with the diaryl sulfide compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine), which impairs the parasite defense against the reactive oxygen

  利什曼原虫是利什曼病的病原体，利什曼病是一种被忽视的热带病，由三种主要临床形式组成：内脏利什曼病（VL），皮肤利什曼病和粘膜皮肤利什曼病。VL由东非和印度次大陆的利什曼原虫donovani以及欧洲，北非和拉丁美洲的婴儿利什曼原虫引起，估计每年导致60,000人死亡。锥虫烷还原酶（TR）被认为是寻找抗利什曼病新药的最佳靶标之一。该酶是人类宿主中寄生虫生存的基础，因为它可减少利什曼原虫的Tryparedoxin / tryparedoxin过氧化物酶系统使用的分子锥虫硫醇。中和宿主巨噬细胞在感染过程中产生的过氧化氢。最近，我们与二芳基硫醚化合物RDS 777（6-（仲丁氧基）-2-（（（3-氯苯基）硫基）嘧啶-4-胺）配合使用，解决了TR的X射线结构，这损害了寄生虫通过高效抑制TR来防御活性氧。该化合物结合到催化位点，并通过氢键结合更多参与催化的残基，即Glu466'，Cys57和Cys52，从而抑制锥虫硫醚的结合。在RDS
• Inhibition of <i>Leishmania infantum</i> trypanothione reductase by diaryl sulfide derivatives
  作者：Francesco Saccoliti、Gabriella Angiulli、Giovanni Pupo、Luca Pescatori、Valentina Noemi Madia、Antonella Messore、Gianni Colotti、Annarita Fiorillo、Luigi Scipione、Marina Gramiccia、Trentina Di Muccio、Roberto Di Santo、Roberta Costi、Andrea Ilari

  DOI：10.1080/14756366.2016.1250755

  日期：2017.1.1

  The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl) thio)pyrimidin-4-amine) (IC50 = 29.43 mu M), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (K-i 0.25 +/- 0.18 mu M). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.