N′-(7-chloroquinolin-4-yl)-N-[(3-diethylamino-propyl)]-nicotinimidamide

• 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: N′-(7-chloroquinolin-4-yl)-N-[(3-diethylamino-propyl)]-nicotinimidamide
• 英文别名: N-(7-chloro-4-quinolyl)-N'-[3-(diethylamino)propyl]pyridine-3-carboxamidine；N-(7-chloroquinolin-4-yl)-N'-[3-(diethylamino)propyl]pyridine-3-carboximidamide
• 化学式: C₂₂H₂₆ClN₅
• 分子量: 395.935
• InChiKey: POSIXXVWRXUWGK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  53.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4,7-二氯喹啉 、 3-甲脒基吡啶盐酸盐 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 反应 7.5h， 生成 N′-(7-chloroquinolin-4-yl)-N-[(3-diethylamino-propyl)]-nicotinimidamide 、 N-(7-chloroquinolin-4-yl)-N,N′-bis[3-(diethylamino)-propyl]-nicotinimidamide
  参考文献：
  名称：

  Antimalarial Activity of 4-Amidinoquinoline and 10-Amidinobenzonaphthyridine Derivatives

  摘要：

  Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk X 3. The best compound shows IC50 < 1 ng/mL against D6, W2 and C235 Pf clones, low inhibitory activity in hERG K+ channel blockage testing, negativity in the Ames test, and 5/5 cure @ <15 mpk X 3 in mice infected with Plasmodium berghei. In addition to these desirable pharmacological profiles, compound 13b, one of the most active compounds, is metabolically stable in both human and mouse liver microsomal preparations and has a plasma t(1/2) of 50 h in mice, which made it a good MQ replacement candidate.

  DOI：

  10.1021/jm501809x

文献信息

• Antimalarial Activity of 4-Amidinoquinoline and 10-Amidinobenzonaphthyridine Derivatives
  作者：Vasiliy Korotchenko、Ramadas Sathunuru、Lucia Gerena、Diana Caridha、Qigui Li、Mara Kreishman-Deitrick、Philip L. Smith、Ai J. Lin

  DOI：10.1021/jm501809x

  日期：2015.4.23

  Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk X 3. The best compound shows IC50 < 1 ng/mL against D6, W2 and C235 Pf clones, low inhibitory activity in hERG K+ channel blockage testing, negativity in the Ames test, and 5/5 cure @ <15 mpk X 3 in mice infected with Plasmodium berghei. In addition to these desirable pharmacological profiles, compound 13b, one of the most active compounds, is metabolically stable in both human and mouse liver microsomal preparations and has a plasma t(1/2) of 50 h in mice, which made it a good MQ replacement candidate.