tert-butyl 4-((2-(2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl)hydrazinecarbonyl)benzo[b]thiophen-3-yl)oxy)piperidine-1-carboxylate | 1443209-38-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 4-((2-(2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl)hydrazinecarbonyl)benzo[b]thiophen-3-yl)oxy)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-[[2-[[[2-(1,3,5-trimethylpyrazol-4-yl)acetyl]amino]carbamoyl]-1-benzothiophen-3-yl]oxy]piperidine-1-carboxylate；tert-butyl 4-[[2-[[[2-(1,3,5-trimethylpyrazol-4-yl)acetyl]amino]carbamoyl]-1-benzothiophen-3-yl]oxy]piperidine-1-carboxylate
• CAS: 1443209-38-8
• 化学式: C₂₇H₃₅N₅O₅S
• 分子量: 541.671
• InChiKey: UOHRKQMJAKULBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-((2-(2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl)hydrazinecarbonyl)benzo[b]thiophen-3-yl)oxy)piperidine-1-carboxylate 在 1,2,2,6,6-五甲基哌啶 、 间甲苯磺酰氯 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole
  参考文献：
  名称：

  Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

  摘要：

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

  DOI：

  10.1021/jm500066b
• 作为产物：
  描述：

  ethyl 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetate 在 lithium hydroxide monohydrate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 tert-butyl 4-((2-(2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl)hydrazinecarbonyl)benzo[b]thiophen-3-yl)oxy)piperidine-1-carboxylate
  参考文献：
  名称：

  Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

  摘要：

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

  DOI：

  10.1021/jm500066b

文献信息

• [EN] NOVEL COMPOUNDS AND THEIR USE IN THERAPY<br/>[FR] NOUVEAUX COMPOSÉS ET LEUR UTILISATION EN THÉRAPIE
  申请人：IMP INNOVATIONS LTD

  公开号：WO2013083991A1

  公开（公告）日：2013-06-13

  The invention provides compounds which inhibit N-myristoyltransferase and are selective for protozoal N-myristoyltransferase and, consequently suitable to treat microbial infections, including viral and fungal infections, and protozoan infections such as malaria, leishmaniasis and sleeping sickness.

  这项发明提供了抑制N-肉豆蔻酰基转移酶并且对原生动物N-肉豆蔻酰基转移酶具有选择性的化合物，因此适用于治疗微生物感染，包括病毒和真菌感染，以及疟疾、利什曼病和睡眠病等原生动物感染。
• Design and Synthesis of High Affinity Inhibitors of <i>Plasmodium falciparum</i> and <i>Plasmodium vivax N</i>-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)
  作者：Mark D. Rackham、James A. Brannigan、Kaveri Rangachari、Stephan Meister、Anthony J. Wilkinson、Anthony A. Holder、Robin J. Leatherbarrow、Edward W. Tate

  DOI：10.1021/jm500066b

  日期：2014.3.27

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.