4-[3-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]benzyl]piperazine-1-carboxylic acid tert-butyl ester | 1295647-22-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-[3-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]benzyl]piperazine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 4-[[3-[(2R,8R)-2-(1,3-benzodioxol-5-yl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-6-yl]phenyl]methyl]piperazine-1-carboxylate
• CAS: 1295647-22-1
• 化学式: C₃₇H₃₉N₅O₆
• 分子量: 649.747
• InChiKey: UUEDJRCLICHXMW-ANHUGMMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  48
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-[3-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]benzyl]piperazine-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 24.0h， 以100%的产率得到(6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-(3-piperazin-1-ylmethylphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione dihydrochloride
  参考文献：
  名称：

  Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

  摘要：

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .

  DOI：

  10.1021/jm1014617
• 作为产物：
  描述：

  D-色氨酸甲酯 在 potassium phosphate 、 copper(l) iodide 、 trans-1,2-Diaminocyclohexane 、 氨 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 360.0h， 生成 4-[3-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]benzyl]piperazine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

  摘要：

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .

  DOI：

  10.1021/jm1014617

文献信息

• Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds
  作者：Terence B. Beghyn、Julie Charton、Florence Leroux、Guillaume Laconde、Arnaud Bourin、Paul Cos、Louis Maes、Benoit Deprez

  DOI：10.1021/jm1014617

  日期：2011.5.12

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .