(3S,6R,12aR)-6-benzo[1,3]dioxol-5-yl-3-(1H-indol-3-ylmethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido-[3,4-b]indole-1,4-dione | 1295647-32-3

• 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: (3S,6R,12aR)-6-benzo[1,3]dioxol-5-yl-3-(1H-indol-3-ylmethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido-[3,4-b]indole-1,4-dione
• 英文别名: (2R,5S,8R)-2-(1,3-benzodioxol-5-yl)-5-(1H-indol-3-ylmethyl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
• CAS: 1295647-32-3
• 化学式: C₃₀H₂₄N₄O₄
• 分子量: 504.545
• InChiKey: AOUKHFHMCXSQCZ-VYKTZEHYSA-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：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  99.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  Fmoc-L-色氨酸 在 哌啶 、 吡啶 、 三聚氟氰 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 (3S,6R,12aR)-6-benzo[1,3]dioxol-5-yl-3-(1H-indol-3-ylmethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido-[3,4-b]indole-1,4-dione
  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 .