5,6-dimethoxy-8-[4-amino-1-methylbutylamino]quinoline | 47136-26-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 5,6-dimethoxy-8-[4-amino-1-methylbutylamino]quinoline
• 英文别名: 5,6-dimethoxy-8-<(4-amino-1-methylbutyl)amino>quinoline；5,6-dimethoxyprimaquine；5-methoxyprimaquine；N¹-(5,6-dimethoxy-[8]quinolyl)-1-methyl-butanediyldiamine；N¹-(5,6-Dimethoxy-[8]chinolyl)-1-methyl-butandiyldiamin；4-N-(5,6-dimethoxyquinolin-8-yl)pentane-1,4-diamine
• CAS: 47136-26-5
• 化学式: C₁₆H₂₃N₃O₂
• 分子量: 289.378
• InChiKey: BKJXJTYXBUSXTA-UHFFFAOYSA-N

物化性质

• 沸点：
  471.6±45.0 °C(Predicted)
• 密度：
  1.137±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  69.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5,6-dimethoxy-8-[4-amino-1-methylbutylamino]quinoline 在 氢溴酸 作用下， 以 水 为溶剂， 反应 6.0h， 生成
  参考文献：
  名称：

  Antimalarial activity of primaquine operates via a two-step biochemical relay

  摘要：

  摘要： 盐酸伯氨喹（PQ）是一种重要的抗疟药，但尽管已经开发了70多年，其作用方式仍不清楚。在这里，我们证明羟基化的PQ代谢物（OH-PQm）对疟原虫的肝和性传播阶段的疗效负责。PQ对肝阶段的抗疟活性取决于宿主CYP2D6状态，而OH-PQm显示出直接的、独立于CYP2D6的活性。PQ需要肝代谢才能对配子体阶段产生活性。OH-PQm对疟原虫配子体的抗疟功效较小，但在肝和骨髓的细胞色素P450 NADPH：氧化还原酶（CPR）的存在下，其效力增强约1000倍。OH-PQm功效的增强是由于CPR对醌亚胺代谢物的直接还原，同时产生大量的H₂O₂，导致疟原虫死亡。这种机制的详细理解为有理重设计具有改进药理特性的8-氨基喹啉铺平了道路。

  DOI：

  10.1038/s41467-019-11239-0
• 作为产物：
  描述：

  2-(4-溴戊基)-1H-异吲哚-1,3-(2H)二酮 在 一水合肼 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 14.0h， 生成 5,6-dimethoxy-8-[4-amino-1-methylbutylamino]quinoline
  参考文献：
  名称：

  Antimalarial activity of primaquine operates via a two-step biochemical relay

  摘要：

  摘要： 盐酸伯氨喹（PQ）是一种重要的抗疟药，但尽管已经开发了70多年，其作用方式仍不清楚。在这里，我们证明羟基化的PQ代谢物（OH-PQm）对疟原虫的肝和性传播阶段的疗效负责。PQ对肝阶段的抗疟活性取决于宿主CYP2D6状态，而OH-PQm显示出直接的、独立于CYP2D6的活性。PQ需要肝代谢才能对配子体阶段产生活性。OH-PQm对疟原虫配子体的抗疟功效较小，但在肝和骨髓的细胞色素P450 NADPH：氧化还原酶（CPR）的存在下，其效力增强约1000倍。OH-PQm功效的增强是由于CPR对醌亚胺代谢物的直接还原，同时产生大量的H₂O₂，导致疟原虫死亡。这种机制的详细理解为有理重设计具有改进药理特性的8-氨基喹啉铺平了道路。

  DOI：

  10.1038/s41467-019-11239-0

文献信息

• Synthesis of certain hydroxy analogs of the antimalarial drug primaquine and their in vitro methemoglobin-producing and glutathione-depleting activity in human erythrocytes
  作者：Reza Allahyari、Allen Strother、Ian M. Fraser、Anthony J. Verbiscar

  DOI：10.1021/jm00369a031

  日期：1984.3

  A number of hydroxy analogues of the antimalarial drug primaquine [8-[(4-amino-1-methylbutyl)amino]-6-methoxyquinoline] were synthesized and characterized by 1H NMR and mass spectra. Several of the compounds were found to be active in forming methemoglobin in human erythrocytes, particularly in those from glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. Decreased levels of glutathione (GSH)

  合成了许多抗疟药伯氨喹[8-[（4-氨基-1-甲基丁基）氨基] -6-甲氧基喹啉]的羟基类似物，并通过1H NMR和质谱表征。发现几种化合物在人红细胞中形成高铁血红蛋白具有活性，特别是在葡萄糖-6-磷酸脱氢酶（G6PD）缺乏者中。还发现具有活性高铁血红蛋白前体的化合物的G6PD缺陷型红细胞中的谷胱甘肽（GSH）含量降低。
• Primaquine-Induced Hemolytic Anemia: Susceptibility of Normal versus Glutathione-Depleted Rat Erythrocytes to 5-Hydroxyprimaquine
  作者：Zachary S. Bowman、John E. Oatis、Jennifer L. Whelan、David J. Jollow、David C. McMillan

  DOI：10.1124/jpet.103.062984

  日期：2004.4

  Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. Methemoglobinemia and hemolytic anemia, however, are dose-limiting side effects of primaquine therapy. These hemotoxic effects are believed to be mediated by metabolites, although the identity of the toxic specie(s) and the mechanism underlying hemotoxicity have remained unclear. Previous studies showed that an N -hydroxylated metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline, was capable of mediating primaquine-induced hemotoxicity. The present studies were undertaken to investigate the hemolytic potential of 5-hydroxyprimaquine (5-HPQ), a phenolic metabolite that has been detected in experimental animals. 5-HPQ was synthesized, isolated by flash chromatography, and characterized by NMR spectroscopy and mass spectrometry. In vitro exposure of 51Cr-labeled erythrocytes to 5-HPQ induced a concentration-dependent decrease in erythrocyte survival (TC50 of ca. 40 μM) when the exposed cells were returned to the circulation of isologous rats. 5-HPQ also induced methemoglobin formation and depletion of glutathione (GSH) when incubated with suspensions of rat erythrocytes. Furthermore, when red cell GSH was depleted (>95%) by titration with diethyl maleate to mimic GSH instability in human glucose-6-phosphate dehydrogenase deficiency, a 5-fold enhancement of hemolytic activity was observed. These data indicate that 5-HPQ also has the requisite properties to contribute to the hemotoxicity of primaquine. The relative contribution of N -hydroxy versus phenolic metabolites to the overall hemotoxicity of primaquine remains to be assessed.

  伯氨喹是一种重要的抗疟疾药物，因为它对疟原虫的外周血形式具有活性。然而，高铁血红蛋白血症和溶血性贫血是伯氨喹治疗的剂量限制性副作用。这些血液毒性效应被认为是由代谢产物介导的，尽管毒性物种和血液毒性机制的性质仍然不清楚。先前的研究表明，伯氨喹的N-羟基代谢产物6-甲氧基-8-羟基氨基喹啉能够介导伯氨喹诱导的血液毒性。本研究旨在调查5-羟基伯氨喹（5-HPQ）的溶血潜力，这是一种在实验动物中检测到的酚类代谢产物。5-HPQ通过快速色谱法合成、分离，并通过核磁共振波谱和质谱进行表征。当暴露的细胞返回同源大鼠的循环时，51Cr标记的红细胞在体外暴露于5-HPQ时，红细胞存活率呈浓度依赖性下降（TC50约为40μM）。当与大鼠红细胞悬浮液一起培养时，5-HPQ还会诱导高铁血红蛋白的形成和谷胱甘肽（GSH）的耗竭。此外，当用马来酸二乙酯滴定红细胞GSH耗竭（>95%）以模拟人类葡萄糖
• Further Syntheses of Primaquine Analogs¹
  作者：Robert C. Elderfield、Elizabeth F. Claflin、Holly E. Mertel、Orville L. McCurdy、Richard T. Mitch、Charles D. Ver Nooy、Bruce H. Wark、Iris M. Wempen

  DOI：10.1021/ja01623a039

  日期：1955.9
• Antimalarial activity of primaquine operates via a two-step biochemical relay
  作者：Grazia Camarda、Piyaporn Jirawatcharadech、Richard S. Priestley、Ahmed Saif、Sandra March、Michael H. L. Wong、Suet Leung、Alex B. Miller、David A. Baker、Pietro Alano、Mark J. I. Paine、Sangeeta N. Bhatia、Paul M. O’Neill、Stephen A. Ward、Giancarlo A. Biagini

  DOI：10.1038/s41467-019-11239-0

  日期：——

  Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H₂O₂, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.

  摘要： 盐酸伯氨喹（PQ）是一种重要的抗疟药，但尽管已经开发了70多年，其作用方式仍不清楚。在这里，我们证明羟基化的PQ代谢物（OH-PQm）对疟原虫的肝和性传播阶段的疗效负责。PQ对肝阶段的抗疟活性取决于宿主CYP2D6状态，而OH-PQm显示出直接的、独立于CYP2D6的活性。PQ需要肝代谢才能对配子体阶段产生活性。OH-PQm对疟原虫配子体的抗疟功效较小，但在肝和骨髓的细胞色素P450 NADPH：氧化还原酶（CPR）的存在下，其效力增强约1000倍。OH-PQm功效的增强是由于CPR对醌亚胺代谢物的直接还原，同时产生大量的H₂O₂，导致疟原虫死亡。这种机制的详细理解为有理重设计具有改进药理特性的8-氨基喹啉铺平了道路。