6-fluoro-2-p-tolylquinoline-4-carboxylic acid | 18060-42-9

• 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: 6-fluoro-2-p-tolylquinoline-4-carboxylic acid
• 英文别名: 2-p-Tolyl-6-fluorchinolin-4-carbonsaeure；2-(p-Tolyl)-6-fluorcinchoninsaeure；6-Fluoro-2-(4-methylphenyl)quinoline-4-carboxylic acid
• CAS: 18060-42-9
• 化学式: C₁₇H₁₂FNO₂
• 分子量: 281.286
• InChiKey: DKRAFRHHWPPQBZ-UHFFFAOYSA-N

物化性质

• 沸点：
  466.2±45.0 °C(Predicted)
• 密度：
  1.307±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2933499090

反应信息

• 作为反应物：
  描述：

  6-fluoro-2-p-tolylquinoline-4-carboxylic acid 在 氯化亚砜 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 生成 6-fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-2-p-tolylquinoline-4-carboxamide
  参考文献：
  名称：

  Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety

  摘要：

  A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC50 values in the single-digit nM range. An analysis of structure activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.001
• 作为产物：
  描述：

  4-fluoroisonitrosoacetanilide 在 硫酸 、 potassium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 生成 6-fluoro-2-p-tolylquinoline-4-carboxylic acid
  参考文献：
  名称：

  Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety

  摘要：

  A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC50 values in the single-digit nM range. An analysis of structure activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.001

文献信息

• Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy
  作者：Beatriz Baragaña、Neil R. Norcross、Caroline Wilson、Achim Porzelle、Irene Hallyburton、Raffaella Grimaldi、Maria Osuna-Cabello、Suzanne Norval、Jennifer Riley、Laste Stojanovski、Frederick R. C. Simeons、Paul G. Wyatt、Michael J. Delves、Stephan Meister、Sandra Duffy、Vicky M. Avery、Elizabeth A. Winzeler、Robert E. Sinden、Sergio Wittlin、Julie A. Frearson、David W. Gray、Alan H. Fairlamb、David Waterson、Simon F. Campbell、Paul Willis、Kevin D. Read、Ian H. Gilbert

  DOI：10.1021/acs.jmedchem.6b00723

  日期：2016.11.10

  The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with

  描述了一系列 quinoline-4-carboxamides 的抗疟原虫活性、DMPK 特性和功效。该系列是从针对恶性疟原虫 (3D7) 血液阶段的表型筛选中确定的，显示出中等效力，但物理化学性质不理想，微粒体稳定性较差。筛选命中 (1, EC50 = 120 nM) 被优化为具有低纳摩尔体外效力的先导分子。药代动力学特征的改进导致几种化合物在伯氏疟原虫疟疾小鼠模型中显示出优异的口服功效，当口服给药 4 天时，ED90 值低于 1 mg/kg。有利的效力、选择性、DMPK 特性和功效，加上新的作用机制，抑制翻译延伸因子 2 (PfEF2)，
• A novel multiple-stage antimalarial agent that inhibits protein synthesis
  作者：Beatriz Baragaña、Irene Hallyburton、Marcus C. S. Lee、Neil R. Norcross、Raffaella Grimaldi、Thomas D. Otto、William R. Proto、Andrew M. Blagborough、Stephan Meister、Grennady Wirjanata、Andrea Ruecker、Leanna M. Upton、Tara S. Abraham、Mariana J. Almeida、Anupam Pradhan、Achim Porzelle、María Santos Martínez、Judith M. Bolscher、Andrew Woodland、Torsten Luksch、Suzanne Norval、Fabio Zuccotto、John Thomas、Frederick Simeons、Laste Stojanovski、Maria Osuna-Cabello、Paddy M. Brock、Tom S. Churcher、Katarzyna A. Sala、Sara E. Zakutansky、María Belén Jiménez-Díaz、Laura Maria Sanz、Jennifer Riley、Rajshekhar Basak、Michael Campbell、Vicky M. Avery、Robert W. Sauerwein、Koen J. Dechering、Rintis Noviyanti、Brice Campo、Julie A. Frearson、Iñigo Angulo-Barturen、Santiago Ferrer-Bazaga、Francisco Javier Gamo、Paul G. Wyatt、Didier Leroy、Peter Siegl、Michael J. Delves、Dennis E. Kyle、Sergio Wittlin、Jutta Marfurt、Ric N. Price、Robert E. Sinden、Elizabeth A. Winzeler、Susan A. Charman、Lidiya Bebrevska、David W. Gray、Simon Campbell、Alan H. Fairlamb、Paul A. Willis、Julian C. Rayner、David A. Fidock、Kevin D. Read、Ian H. Gilbert

  DOI：10.1038/nature14451

  日期：2015.6.18

  There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery. The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission. With artemisinin resistance spreading, there is an urgent need to develop new therapeutics to target Plasmodium falciparum, the causative agent of malaria. Here Ian Gilbert and colleagues report the discovery of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of the parasite and good pharmacokinetic and safety properties. It is non-mutagenic and has potential for both single-dose treatment and once-weekly chemoprotection. DDD107498 acts through inhibition of cytosolic protein synthesis, with translation elongation factor eEF2 as its target.

  迫切需要新药物来治疗疟疾，这些药物应具有广泛的治疗潜力和新颖的作用机制，以扩大治疗范围并克服新出现的药物耐药性。在这里，我们描述了DDD107498的发现，这是一种对多种疟原虫生命周期阶段具有强效和新颖抗疟活性的化合物，其药代动力学性质良好并且安全性可接受。DDD107498展现了满足多种临床需求的潜力，包括单剂量治疗、传播阻断和化学保护。DDD107498是在针对血液阶段疟原虫的筛选项目中开发的，其分子靶标已确定为翻译延伸因子2（eEF2），该因子负责GTP依赖的核糖体沿信使RNA的转位，并对蛋白质合成至关重要。将eEF2发现为一个可行的抗疟药物靶标，开启了药物发现的新可能性。DDD107498是一种对多种疟原虫生命周期阶段具有抗疟活性、药代动力学和安全性良好的化合物，具有单剂量治疗、化学保护和预防传播的潜力。随着青蒿素耐药性的传播，迫切需要开发新疗法以针对引起疟疾的疟原虫。在这里，Ian Gilbert和他的同事报告了一种具有对疟原虫多个生命周期阶段抗疟活性且具有良好药代动力学和安全性特性的化合物（DDD107498）的发现。该化合物无诱变性，有潜力用于单剂量治疗和每周一次的化学保护。DDD107498通过抑制细胞质蛋白质合成发挥作用，其靶标是翻译延伸因子eEF2。
• Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety
  作者：Sai Li、Qiang Huang、Yajing Liu、Xiaolong Zhang、Shuang Liu、Chao He、Ping Gong

  DOI：10.1016/j.ejmech.2013.04.001

  日期：2013.6

  A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC50 values in the single-digit nM range. An analysis of structure activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity. (C) 2013 Elsevier Masson SAS. All rights reserved.