4'-N-(tert-butoxycarbonyl-L-alanyl)primaquine | 193896-31-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4'-N-(tert-butoxycarbonyl-L-alanyl)primaquine
• 英文别名: N-{7-[(6-methoxyquinolin-8-yl)amino]-3-aza-1-methyl-2-oxooctyl}carbamic acid tert-butyl ester；tert-butyl (S)-1-(4-(6-methoxyquinolin-8-ylamino)pentylamino)-1-oxopropan-2-ylcarbamate；N-(Nα-Boc-alanyl)primaquine
• CAS: 193896-31-0
• 化学式: C₂₃H₃₄N₄O₄
• 分子量: 430.547
• InChiKey: OBXYCVIVHGCDII-LYKKTTPLSA-N

物化性质

• 沸点：
  663.4±55.0 °C(Predicted)
• 密度：
  1.140±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.85
• 重原子数：
  31.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  101.58
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4'-N-(tert-butoxycarbonyl-L-alanyl)primaquine 在 4 A molecular sieve 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 为溶剂， 反应 72.0h， 生成 3-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-3-methyl-1,4-diazaspiro[4.4]nonan-2-one
  参考文献：
  名称：

  伯氨喹的咪唑啉丁-4-酮和1 H-咪唑并[2,1 - a ]异吲哚-2,5（3 H，9b H）-二酮衍生物的合成：范围和局限性

  摘要：

  描述了伯氨喹的咪唑啉丁-4-酮衍生物作为潜在的抗疟药的合成。在三个步骤中合成的目标化合物：（ⅰ）的缩合（±）-primaquine用N α -保护的氨基酸，（ⅱ）除去N-的α保护基团，和（iii）的N acylprimaquine与反应羰基化合物：丙酮，三个环酮和藜芦醛。在得到第三步骤，使用2-甲酰基苯甲酸1 H ^ -咪唑并[2,1-一个]异吲哚-2,5（3 ħ，9B ħ） -二酮。分离出的所有产物均具有良好的收率。咪唑啉丁-4-酮是所有可能的非对映异构体的等量混合物，而1 H-咪唑并[2,1-以立体选择性的方式产生]异吲哚-2,5（3 H，9b H）-二酮。化合物在pH 7.4缓冲液中水解非常缓慢（t 1/2 5–30 d），释放出伯氨喹。这些伯氨喹衍生物正在接受生物学检测，其抗疟活性的初步结果令人鼓舞。

  DOI：

  10.1016/j.tet.2004.04.077
• 作为产物：
  描述：

  N-叔丁氧羰基-L-丙氨酸 、 伯氨喹 在 N-甲基吗啉 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 生成 4'-N-(tert-butoxycarbonyl-L-alanyl)primaquine
  参考文献：
  名称：

  Discovery of oxybisbenzoylamides as a new class of antimalarial agents

  摘要：

  从先前描述的疟原虫的双重抑制剂出发，得到了一种新的抗疟药物药效团。

  DOI：

  10.1039/c5md00115c

文献信息

• Imidazolidin-4-one peptidomimetic derivatives of primaquine: Synthesis and antimalarial activity
  作者：Nuno Vale、Joana Matos、Jiri Gut、Fátima Nogueira、Virgílio do Rosário、Philip J. Rosenthal、Rui Moreira、Paula Gomes

  DOI：10.1016/j.bmcl.2008.05.076

  日期：2008.7

  The synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in

  描述了在与母体药物偶联的二肽主链的C末端含有五元环的伯氨喹的咪唑烷二-4-酮衍生物的合成。这些拟肽衍生物对抗氯喹的恶性疟原虫菌株具有活性，并抑制了伯氏疟原虫的孢子周期的发展，影响了蚊子中肠内卵囊的出现。由于N（1）的酰化作用，新型的咪唑烷基-4-酮在人血浆和pH 7.4缓冲液中都极为稳定。因此，衍生自二肽基8-氨基喹啉的“内部”咪唑啉丁-4-酮代表了抗疟疾结构-活性关系中的一个新条目。
• Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs
  作者：Nuno Vale、Fátima Nogueira、Virgílio E. do Rosário、Paula Gomes、Rui Moreira

  DOI：10.1016/j.ejmech.2009.01.018

  日期：2009.6

  Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. All compounds were hydrolyzed to the parent dipeptide derivative of primaquine in neutral and basic solutions, with half lives ranging from 0.7 to 31 h at 37 °C, depending on the nature of the substituents present in the imidazolidin-4-one

  合成了在N-末端带有咪唑烷基-4-酮部分的伯氨喹二肽衍生物，并将其评估为潜在的阻断传导的抗疟原药。所有化合物均在中性和碱性溶液中水解为伯氨喹的母体二肽衍生物，其半衰期在37°C下为0.7至31 h，具体取决于咪唑烷酮-4-one部分和烷基中存在的取代基的性质。 C端氨基酸直接偶联至伯氨喹。使用由伯氏疟原虫，BalbC小鼠和按蚊按蚊组成的模型研究了所选化合物的抗疟活性蚊子。由丙氨酸-丙氨酸伯氨喹和丙酮衍生的咪唑啉丁-4-酮比伯氨喹更有效地减少了感染向蚊子的传播，这表现为蚊子中肠中的卵囊数量显着减少，分别为10和50μmol/与对照相比，kg。
• Novel Potent Metallocenes against Liver Stage Malaria
  作者：Joana Matos、Filipa P. da Cruz、Élia Cabrita、Jiri Gut、Fátima Nogueira、Virgílio E. do Rosário、Rui Moreira、Philip J. Rosenthal、Miguel Prudêncio、Paula Gomes

  DOI：10.1128/aac.05345-11

  日期：2012.3

  Novel conjugates of the antimalarial drug primaquine (compound 1) with ferrocene, named primacenes, have been synthesized and screened for their activities against blood stage and liver stage malaria in vitro and host-vector transmission in vivo . Both transmission-blocking and blood-schizontocidal activities of the parent drug were conserved only in primacenes bearing a basic aliphatic amine group. Liver stage activity did not require this structural feature, and all metallocenes tested were comparable to or better than primaquine in this regard. Remarkably, the replacement of primaquine's aliphatic chain by hexylferrocene, as in compound 7, led to a ∼45-fold-higher level activity against liver stage parasitemia than that of primaquine.

  摘要 合成了抗疟药物伯氨喹（化合物 1）与二茂铁的新型共轭物，命名为二茂铁骁悉，并筛选了其对血期和肝期疟疾的活性。 体外 和宿主-病媒传播 体内 .母体药物的传播阻断和血吸虫杀灭活性只有在含有碱性脂肪胺基团的原烯中才得以保留。肝脏阶段的活性并不需要这一结构特征，所有测试过的茂金属在这方面都与伯氨喹相当或优于伯氨喹。值得注意的是，用二茂铁己基取代伯氨喹的脂肪链（如化合物 7），对肝阶段寄生虫血症的活性比伯氨喹高出 45 倍。
• Synthesis and in Vitro Evaluation of Potential Antichagasic Dipeptide Prodrugs of Primaquine
  作者：M.C. Chung、M.F. Gonçalves、W. Colli、E.I. Ferreira、M.T.M. Miranda

  DOI：10.1021/js970006v

  日期：1997.10

  American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million people in Latin America. Currently, therapy is unsatisfactory and only two drugs are available. Primaquine, an antimalarial drug, has trypanocidal activity. Dipeptide derivatives of primaquine, Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ, were synthesized. The choice of the peptides was based on the primary specificity of cruzipain, the major cysteine proteinase from T. cruzi. The prodrugs obtained were tested on the LLC-MK2 cell culture infected with trypomastigotes forms of T. cruzi Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ were active in all stages.
• High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors
  作者：Mario Dell'Agli、Silvia Parapini、Germana Galli、Nadia Vaiana、Donatella Taramelli、Anna Sparatore、Peng Liu、Ben M. Dunn、Enrica Bosisio、Sergio Romeo

  DOI：10.1021/jm061033d

  日期：2006.12.1

  The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the "double-drug" approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC50) as low as 0.1 mu M was obtained, an excellent improvement in comparison with inhibitors previously reported (IC50 = 2 - 20 mu M). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K-i = 1 - 700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 mu M and were highly selective for PLMs vs human cathepsin D.