3-(2-(benzyloxy)-8-methylquinolin-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine | 1574256-79-3

• 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: 3-(2-(benzyloxy)-8-methylquinolin-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: 3-[2-(Benzyloxy)-8-Methylquinolin-6-Yl]-1-(Propan-2-Yl)-1h-Pyrazolo[3,4-D]pyrimidin-4-Amine；3-(8-methyl-2-phenylmethoxyquinolin-6-yl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1574256-79-3
• 化学式: C₂₅H₂₄N₆O
• 分子量: 424.505
• InChiKey: QJSJMPRJBAGLJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  91.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-bromo-8-methyl-2(1H)-quinolinone 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 potassium acetate 、 sodium carbonate 、 caesium carbonate 、 silver carbonate 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 49.0h， 生成 3-(2-(benzyloxy)-8-methylquinolin-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

  摘要：

  Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein lcinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATPbinding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.12.048

文献信息

• Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes
  作者：Rama Subba Rao Vidadala、Kayode K. Ojo、Steven M. Johnson、Zhongsheng Zhang、Stephen E. Leonard、Arinjay Mitra、Ryan Choi、Molly C. Reid、Katelyn R. Keyloun、Anna M.W. Fox、Mark Kennedy、Tiffany Silver-Brace、Jen C.C. Hume、Stefan Kappe、Christophe L.M.J. Verlinde、Erkang Fan、Ethan A. Merritt、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1016/j.ejmech.2013.12.048

  日期：2014.3

  Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein lcinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATPbinding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria. (C) 2014 Elsevier Masson SAS. All rights reserved.