2-[4-[(7-chloro-4-quinolyl)amino]pentyl(ethyl)amino]ethyl-6-[2-(3-methyl)-1,4-naphthoquinolyl]hexanoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-[4-[(7-chloro-4-quinolyl)amino]pentyl(ethyl)amino]ethyl-6-[2-(3-methyl)-1,4-naphthoquinolyl]hexanoate
• 英文别名: 2-[4-[(7-Chloroquinolin-4-yl)amino]pentyl-ethylamino]ethyl 6-(3-methyl-1,4-dioxonaphthalen-2-yl)hexanoate
• 化学式: C₃₅H₄₂ClN₃O₄
• 分子量: 604.189
• InChiKey: IGJNWMKEARZYGQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  43
• 可旋转键数：
  17
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  88.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  硫酸羟氯喹 、 6‐(3‐methyl‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)hexanoic acid 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以53%的产率得到2-[4-[(7-chloro-4-quinolyl)amino]pentyl(ethyl)amino]ethyl-6-[2-(3-methyl)-1,4-naphthoquinolyl]hexanoate
  参考文献：
  名称：

  A Prodrug Form of a Plasmodium falciparum Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline

  摘要：

  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.

  DOI：

  10.1021/jm010268g

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.