N-[3-(7-Chloro-quinolin-4-ylamino)-5-hydroxymethyl-phenyl]-2-piperidin-1-yl-acetamide | 362054-04-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[3-(7-Chloro-quinolin-4-ylamino)-5-hydroxymethyl-phenyl]-2-piperidin-1-yl-acetamide
• 英文别名: N-[3-[(7-chloroquinolin-4-yl)amino]-5-(hydroxymethyl)phenyl]-2-piperidin-1-ylacetamide
• CAS: 362054-04-4
• 化学式: C₂₃H₂₅ClN₄O₂
• 分子量: 424.93
• InChiKey: XFHCCMSULFLQGX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  77.5
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[3-(7-Chloro-quinolin-4-ylamino)-5-hydroxymethyl-phenyl]-2-piperidin-1-yl-acetamide 在 chromium(VI) oxide 、 过碘酸 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以90%的产率得到3-[(7-Chloroquinolin-4-yl)amino]-5-[(2-piperidin-1-ylacetyl)amino]benzoic acid
  参考文献：
  名称：

  4-苯胺基喹啉的氨基甲酸酯和酰胺衍生物的合成及其抗疟活性。

  摘要：

  合成了一系列带有通过氨基甲酸酯或酰胺键与芳香环连接的氨基侧链的4-苯胺基喹啉，并评估了它们的抗疟活性和对MRC-5细胞的细胞毒性。在这17种化合物中，大多数化合物在体外对恶性疟原虫的氯喹敏感和耐药菌株具有较低的纳摩尔浓度，且具有较低的细胞毒性。然后在受伯氏疟原虫感染的小鼠上测试了两种化合物，发现它们具有合理的体内活性。

  DOI：

  10.1016/j.ejmech.2007.11.003
• 作为产物：
  描述：

  4,7-二氯喹啉 在 N-乙基哌啶 、 N-甲基吗啉 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 作用下， 以 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 91.0h， 生成 N-[3-(7-Chloro-quinolin-4-ylamino)-5-hydroxymethyl-phenyl]-2-piperidin-1-yl-acetamide
  参考文献：
  名称：

  Synthesis and in Vitro and in Vivo Antimalarial Activity of New 4-Anilinoquinolines

  摘要：

  A new series of 4-anilinoquinolines with two proton-accepting side chains has been synthesized. Antimalarial activity and levels of cytotoxicity upon both MRC-5 cells and macrophages were found to be highly dependent upon the features of these side chains. Several compounds were found to be active in the low nanomolar range, against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. From among them, a morpholino derivative cured mice infected by Plasmodium berghei and displayed a lower toxicity than amodiaquine upon mouse macrophages.

  DOI：

  10.1021/jm010842o

文献信息

• A Prodrug Form of a <i>Plasmodium falciparum </i>Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline
  作者：Elisabeth Davioud-Charvet、Sandrine Delarue、Christophe Biot、Babett Schwöbel、Catharina C. Boehme、Andreas Müssigbrodt、Louis Maes、Christian Sergheraert、Philippe Grellier、R. Heiner Schirmer、Katja Becker

  DOI：10.1021/jm010268g

  日期：2001.11.1

  Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED50 values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED50 being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.
• Synthesis and in Vitro and in Vivo Antimalarial Activity of New 4-Anilinoquinolines
  作者：Sandrine Delarue、Sophie Girault、Louis Maes、Marie-Ange Debreu-Fontaine、Mehdi Labaeïd、Philippe Grellier、Christian Sergheraert

  DOI：10.1021/jm010842o

  日期：2001.8.1

  A new series of 4-anilinoquinolines with two proton-accepting side chains has been synthesized. Antimalarial activity and levels of cytotoxicity upon both MRC-5 cells and macrophages were found to be highly dependent upon the features of these side chains. Several compounds were found to be active in the low nanomolar range, against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. From among them, a morpholino derivative cured mice infected by Plasmodium berghei and displayed a lower toxicity than amodiaquine upon mouse macrophages.
• Synthesis and antimalarial activity of carbamate and amide derivatives of 4-anilinoquinoline
  作者：Sandrine Delarue-Cochin、Philippe Grellier、Louis Maes、Elisabeth Mouray、Christian Sergheraert、Patricia Melnyk

  DOI：10.1016/j.ejmech.2007.11.003

  日期：2008.10

  A series of 4-anilinoquinolines bearing an amino side chain linked to the aromatic ring with a carbamate or an amide bond were synthesized and evaluated for their antimalarial activity and their cytotoxicity upon MRC-5 cells. Among the 17 compounds, a majority was found to be active in the low nanomolar range against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro

  合成了一系列带有通过氨基甲酸酯或酰胺键与芳香环连接的氨基侧链的4-苯胺基喹啉，并评估了它们的抗疟活性和对MRC-5细胞的细胞毒性。在这17种化合物中，大多数化合物在体外对恶性疟原虫的氯喹敏感和耐药菌株具有较低的纳摩尔浓度，且具有较低的细胞毒性。然后在受伯氏疟原虫感染的小鼠上测试了两种化合物，发现它们具有合理的体内活性。