1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(dimethylamino)ethylamino)ethanol | 1258387-06-2

• 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: 1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(dimethylamino)ethylamino)ethanol
• 英文别名: WR 308386；1-[2,8-Bis(trifluoromethyl)quinolin-4-yl]-2-[2-(dimethylamino)ethylamino]ethanol
• CAS: 1258387-06-2
• 化学式: C₁₇H₁₉F₆N₃O
• 分子量: 395.348
• InChiKey: YXHSZZPOIVFHSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  48.4
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2,8-双(三氟甲基)-4-羟基喹啉 在 tris-(dibenzylideneacetone)dipalladium(0) 、 三叔丁基膦 、 potassium carbonate 、 间氯过氧苯甲酸 、 三溴氧磷 作用下， 以 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 6.75h， 生成 1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(dimethylamino)ethylamino)ethanol
  参考文献：
  名称：

  Structure–Activity Relationships of 4-Position Diamine Quinoline Methanols as Intermittent Preventative Treatment (IPT) against Plasmodium falciparum

  摘要：

  A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.

  DOI：

  10.1021/jm200647u

文献信息

• Parallel inhibition of amino acid efflux and growth of erythrocytic Plasmodium falciparum by mefloquine and non-piperidine analogs: Implication for the mechanism of antimalarial action
  作者：Maryam Ghavami、Christie H. Dapper、Seema Dalal、Kristina Holzschneider、Michael Klemba、Paul R. Carlier

  DOI：10.1016/j.bmcl.2016.08.005

  日期：2016.10

  non-piperidine analogs on amino acid efflux and parasite growth. Among these closely related compounds, an excellent correlation over nearly 4 log units is seen for 50% inhibition concentration (IC50) values for parasite growth and leucine efflux. These data and other observations are consistent with the hypothesis that the antimalarial action of these compounds derives from inhibition of hemoglobin endocytosis

  尽管甲氧喹（MQ）在某些患者中引起令人不安的精神副作用，但由于其对所有疟原虫的活性，给药方便性以及对儿童和孕妇的相对安全性，已被用于疟疾的预防和治疗。然而，目前尚无关于MQ的抗疟疾作用机制的共识。MQ机制的两个主要假设是抑制血红素结晶和抑制宿主细胞血红蛋白内吞作用。在本报告中，我们显示MQ是一种有效且快速的氨基酸，可从完整的寄生红细胞中排出氨基酸，这是衡量宿主血红蛋白内吞和分解代谢体内速率的一种方法。为了进一步探讨MQ的作用机理，我们比较了MQ和18个非哌啶类似物对氨基酸外排和寄生虫生长的影响。在这些密切相关的化合物中，对于寄生虫生长和亮氨酸外排的50％抑制浓度（IC50）值，观察到了近4个对数单位的极佳相关性。这些数据和其他观察结果与以下假设相吻合：这些化合物的抗疟疾作用源自抑制血红蛋白内吞作用。
• [EN] NEXT GENERATION QUINOLOINE METHANOLS<br/>[FR] QUINOLÉINE MÉTHANOLS DE NOUVELLE GÉNÉRATION
  申请人：US OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE ARMY ON BEHALF OF U S

  公开号：WO2010144101A1

  公开（公告）日：2010-12-16

  The present invention relates to new quinoline methanol derivatives and therapeutic compostions comprising one or more quinoline methanol derivatives. These compositons are useful in the reduction, treatment, or prevention of malaria, microbial, parasitic, protozoan, bacterial, and fungal diseases and conditions. Advantageously, compositions of the invention are less able to cross the blood-brain barrier than mefloquine and as a result produce fewer adverse side effects to the central nervous system as compared to mefloquine.
• [EN] PENTAFLUOROSULFANYL ANALOGS OF MEFLOQUINE<br/>[FR] ANALOGUES DE PENTAFLUOROSULFANYLE DE LA MÉFLOQUINE
  申请人：US OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE ARMY ON BEHALF OF U S ARMY MEDICAL RES AND MATE

  公开号：WO2010144102A1

  公开（公告）日：2010-12-16

  The present invention relates to new mefloquine derivatives and therapeutic compositions comprising one or more mefloquine derivatives. Mefloquine derivatives of the invention have at least one pentafluorosulfanyl moiety substitution at the 6 or 7 or 8 position. Certain mefloquine derivatives further include a quinoline methonal moiety substitution at the 4 position. These compositions are useful in the reduction, treatment, or prevention of malaria, microbial, parasitic, protozoan, bacterial, and fungal diseases and conditions. Advantageously, compositions of the invention are less able to cross the blood-brain barrier than mefloquine and as a result produce fewer adverse side effects to the central nervous system as compared to mefloquine.
• Structure–Activity Relationships of 4-Position Diamine Quinoline Methanols as Intermittent Preventative Treatment (IPT) against <i>Plasmodium falciparum</i>
  作者：Erin Milner、Sean Gardner、Jay Moon、Kristina Grauer、Jennifer Auschwitz、Ian Bathurst、Diana Caridha、Lucia Gerena、Montip Gettayacamin、Jacob Johnson、Michael Kozar、Patricia Lee、Susan Leed、Qigui Li、William McCalmont、Victor Melendez、Norma Roncal、Richard Sciotti、Bryan Smith、Jason Sousa、Anchalee Tungtaeng、Peter Wipf、Geoffrey Dow

  DOI：10.1021/jm200647u

  日期：2011.9.22

  A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.