N-(3-bromopropyl)-7-chloroquinolin-4-amine | 60548-23-4

• 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-(3-bromopropyl)-7-chloroquinolin-4-amine
• CAS: 60548-23-4
• 化学式: C₁₂H₁₂BrClN₂
• 分子量: 299.598
• InChiKey: OJNLRLKOOJSUHH-UHFFFAOYSA-N

物化性质

• 沸点：
  434.5±40.0 °C(Predicted)
• 密度：
  1.541±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-乙基-5H-[1,2,4]三嗪并[5,6-b]吲哚-3-硫醇 、 N-(3-bromopropyl)-7-chloroquinolin-4-amine 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 80.5h， 以87%的产率得到7-chloro-N-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)quinolin-4-amine
  参考文献：
  名称：

  Triazino indole–quinoline hybrid: A novel approach to antileishmanial agents

  摘要：

  A novel series of 1,2,4-triazino-[5,6b] indole-3-thione covalently linked to 7-chloro-4-aminoquinoline have been synthesized and evaluated for their in vitro activity against extracellular promastigote and intracellular amastigote form of Leishmania donovani. Among all tested compounds, compounds 7a and 7b were found to be the most active with IC50 values 1.11, 0.36 mu M and selectivity index (SI) values 67, >1111, respectively, against amastigote form of L. donovani which is several folds more potent than the standard drugs, miltefosine (IC50 = 8.10 mu M, SI = 7) and sodium stibo-gluconate (IC50 = 54.60 mu M, SI >= 7). (C) 2013 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.11.018
• 作为产物：
  描述：

  7-氯-4-羟基喹啉 在 硫酸 、 氢溴酸 、 三氯氧磷 作用下， 以 neat (no solvent) 为溶剂， 反应 3.0h， 生成 N-(3-bromopropyl)-7-chloroquinolin-4-amine
  参考文献：
  名称：

  设计，合成和生物学评估4-氨基喹啉-胍基硫脲衍生物作为抗疟剂。

  摘要：

  鸟嘌呤硫脲（GTU）已被确定为重要的抗叶酸抗疟药效基团，而4-氨基喹诺酮类药物具有抗疟活性。在本工作中，使用Pf DHFR酶和血红素单元进行分子对接分析，设计了带有4-氨基喹啉和GTU部分的分子。对接结果表明，必要的相互作用（Asp54和Ile14）和对接得分（-9.63至-7.36 kcal / mmol）与WR99210（-9.89 kcal / mol）相当。从这些结果中，选择了九个分子进行合成。在体外，这些合成的化合物的分析揭示出了9个分子的，八显示在0.61-7.55微米的范围抗疟活性Pf的D6应变和0.43-8.04μM为Pf的W2株。此外，对活性最高的分子进行了分子动力学模拟，以建立这些化合物和参考配体与恶性疟原虫二氢叶酸还原酶（Pf DHFR）的比较结合相互作用。

  DOI：

  10.1016/j.bioorg.2019.103094

文献信息

• Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains
  作者：Bruno Tasso、Federica Novelli、Michele Tonelli、Anna Barteselli、Nicoletta Basilico、Silvia Parapini、Donatella Taramelli、Anna Sparatore、Fabio Sparatore

  DOI：10.1002/cmdc.201500195

  日期：2015.9

  Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria‐related deaths, has developed resistance against this drug. Twenty‐seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro‐2H‐quinolizine and 1,2,3,4,5,6‐hexahydro‐1,5‐methano‐8H‐pyrido[1,2‐a][1

  氯喹通常用于治疗和预防疟疾，但是造成疟疾相关死亡的主要物种恶性疟原虫已对该药产生耐药性。二十七种新颖的氯喹（CQ）类似物，特征在于侧链以庞大的基本头基终止，即八氢-2 H-喹啉和1,2,3,4,5,6-六氢-1,5-甲基合成了8 H-吡啶并[1,2- a ] [1,5]重氮星-8-one，并测试了其对P的D-10（CQ敏感）和W-2（CQ抗性）菌株的活性。恶性疟原虫。使用纳摩尔或亚摩尔浓度的IC 50，发现大多数化合物对两种菌株均具有活性价值观。发现有11种化合物对W-2菌株的效力比CQ高2.7至13.4倍；其中，四种半胱氨酸衍生物似乎特别受关注，因为它们结合了对两种人类细胞系（HMEC-1和HepG2）的高效力和低细胞毒性，并且易于合成。用硫桥取代4-NH基团可保持较低的抗血浆活性，但提高了抗性因子。这些化合物作为抗击疟疾的潜在药物值得进一步研究。
• Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents
  作者：P. Linga Reddy、Shabana I. Khan、Prija Ponnan、Mohit Tripathi、Diwan S. Rawat

  DOI：10.1016/j.ejmech.2016.11.057

  日期：2017.1

  were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized

  一种新颖的一系列4-氨基喹啉嘌呤杂交合成并评价了它们对的CQ-敏感和CQ抗性株抗疟原虫活性P。恶性肿瘤。设想将4-氨基喹啉药效团（靶向疟原虫的血红素-解毒途径）与嘌呤功能性（靶向血浆HG（X）PRT酶）连接将产生具有增强效力的杂合抗血浆剂。将合成的杂种显示针对两者的敏感和抗性菌株的良好抗疟原虫活性P。与参考药物CQ（IC）相比，具有更好的六倍活性（化合物10i，IC 50：0.08μM）的恶性疟原虫50：0.5μM）抗性菌株。还检查了合成的化合物对哺乳动物细胞的细胞毒性，除了二十个合成的杂合物中的两种化合物外，其他所有化合物在至多11.86μM的浓度下均无细胞毒性。进行了机制血红素结合研究，以确定合成分子的作用机理，并观察到良好的结合相互作用。计算对接研究表明，最活跃的杂种很好地对接在HGPRT蛋白的结合位点内。在计算机模拟ADME中，对最活跃的杂种的预测表明，这些化合物具有良好的药代动力学行为。
• Dual molecules containing peroxy derivative, the synthesis and therapeutic applications thereof
  申请人：Cazelles Jerome

  公开号：US20070021423A1

  公开（公告）日：2007-01-25

  The invention relates to dual molecule compounds containing a peroxide derivative, to processes for the synthesis of such compounds, to pharmaceutical compositions comprising such compounds, and to methods of treatment and prevention of malaria comprising administering such compounds and such pharmaceutical compositions.

  这项发明涉及含有过氧化物衍生物的双分子化合物，涉及合成这种化合物的方法，涉及包括这种化合物的药物组合物，以及涉及通过给予这种化合物和这种药物组合物来治疗和预防疟疾的方法。
• 10.3390/molecules29132997
  作者：Krstulović, Luka、Rastija, Vesna、Pessanha de Carvalho, Lais、Held, Jana、Rajić, Zrinka、Živković, Zorislava、Bajić, Miroslav、Glavaš-Obrovac, Ljubica

  DOI：10.3390/molecules29132997

  日期：——

  value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure–activity

  新合成的 7-氯-4-氨基喹啉-苯并咪唑杂化物通过核磁共振和元素分析进行​​了表征。测试了化合物对非肿瘤细胞系 MRC-5（人胎儿肺成纤维细胞）和癌（HeLa 和 CaCo-2）、白血病和淋巴瘤（Hut78、THP-1 和 HL-60）生长的影响）细胞系。获得的结果以实现 50% 细胞生长抑制的浓度（IC50 值）表示，表明测试化合物对细胞生长的影响不同，具体取决于细胞系和所用剂量（IC50 范围为 0.2 至 >100 µM） ）。此外，还针对两种恶性疟原虫菌株（Pf3D7 和 PfDd2）评估了这些杂种的抗疟原虫活性。测试的化合物在纳摩尔浓度下对两种菌株都显示出有效的抗疟原虫活性。定量构效关系 (QSAR) 分析得出了针对 3D7 菌株（R2 = 0.886；Rext2 = 0.937；F = 41.589）和 Dd2 菌株（R2 = 0.859；Rext2 = 0.878；F = 32
• A chloroquinoline derivate presents effective in vitro and in vivo antileishmanial activity against Leishmania species that cause tegumentary and visceral leishmaniasis
  作者：Jessica K.T. Sousa、Luciana M.R. Antinarelli、Débora V.C. Mendonça、Daniela P. Lage、Grasiele S.V. Tavares、Daniel S. Dias、Patrícia A.F. Ribeiro、Fernanda Ludolf、Vinicio T.S. Coelho、João A. Oliveira-da-Silva、Luísa Perin、Bianka A. Oliveira、Denis F. Alvarenga、Miguel A. Chávez-Fumagalli、Geraldo C. Brandão、Vandack Nobre、Guilherme R. Pereira、Elaine S. Coimbra、Eduardo A.F. Coelho

  DOI：10.1016/j.parint.2019.101966

  日期：2019.12

  The identification of new therapeutics to treat leishmaniasis is desirable,,since available drugs are toxic and present high cost and/or poor availability. Therefore, the discovery of safer, more effective and selective pharmaceutical options is of utmost importance. Efforts towards the development of new candidates based on molecule analogs with known biological functions have been an interesting and cost-effective strategy. In this context, quinoline derivatives have proven to be effective biological activities against distinct diseases. In the present study, a new chloroquinoline derivate, AM1009, was in vitro tested against two Leishmania species that cause leishmaniasis. The present study analyzed the necessary inhibitory concentration to preclude 50% of the Leishmania promastigotes and axenic amastigotes (EC50 value), as well as the inhibitory concentrations to preclude 50% of the murine macrophages and human red blood cells (CC50 and RBC50 values, respectively). In addition, the treatment of infected macrophages and the inhibition of infection using pre-treated parasites were also investigated, as was the mechanism of action of the molecule in L. amazonensis. To investigate the in vivo therapeutic effect, BALB/c mice were infected with L. amazonensis and later treated with AM1009. Parasitological and immunological parameters were also evaluated. Clioquinol, a known antileishmanial quinoline derivate, and amphotericin B (AmpB), were used as molecule and drug controls, respectively. Results in both in vitro and in vivo experiments showed a better and more selective action of AM1009 to kill the in vitro parasites, as well as in treating infected mice, when compared to results obtained using clioquinol or AmpB. AM1009-treated animals presented significantly lower average lesion diameter and parasite burden in the infected tissue and organs evaluated in this study, as well as a more polarized antileishmanial Th1 immune response and low renal and hepatic toxicity. This result suggests that AM1009 should be considered a possible therapeutic target to be evaluated in future studies for treatment against leishmaniasis.