2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-methoxyaniline | 1361005-87-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-methoxyaniline
• 英文别名: 2-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-5-methoxyaniline
• CAS: 1361005-87-9
• 化学式: C₁₂H₁₆N₂O₂
• 分子量: 220.271
• InChiKey: BMEOFIUFZHLBEA-UHFFFAOYSA-N

物化性质

• 沸点：
  363.5±32.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-methoxyaniline 、 1-(4-(4-(trifluoromethoxy)benzyl)phenyl)propan-1-one 在 三溴化硼 、 对甲苯磺酸 作用下， 以 二氯甲烷 、 正丁醇 为溶剂， 反应 48.0h， 生成 7-hydroxy-3-methyl-2-[4-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-1H-quinolin-4-one
  参考文献：
  名称：

  靶向恶性疟原虫 II 型 NADH:醌氧化还原酶 (PfNDH2) 的双芳基喹诺酮类药物的鉴定、设计和生物学评价

  摘要：

  进行了一项计划来鉴定针对 NADH 的命中化合物：泛醌氧化还原酶 (PfNDH2)，这是一种疟疾寄生虫恶性疟原虫线粒体电子传递链的脱氢酶. PfNDH2 只有一种已知抑制剂，羟基-2-十二烷基-4-(1H)-喹诺酮 (HDQ)，它与一系列化学信息学方法一起用于合理选择 17000 种化合物以进行高通量筛选。确定并简要检查了 12 种不同的化学型，导致选择喹诺酮核心作为构效关系 (SAR) 发展的关键目标。广泛的结构探索导致选择 2-双芳基 3-甲基喹诺酮作为进一步生物学评价的系列。该系列中的先导化合物 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) 对 3D7 具有抗疟活性36 nM 的恶性疟原虫菌株对 PfNDH2 的选择性高于其他呼吸酶（抑制性 IC50对 PfNDH2

  DOI：

  10.1021/jm201179h
• 作为产物：
  描述：

  2-氨基-4-甲氧基苯甲酸 在 zinc(II) chloride 作用下， 以 四氢呋喃 、 水 、 氯苯 为溶剂， 反应 26.0h， 生成 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-methoxyaniline
  参考文献：
  名称：

  2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

  摘要：

  描述了具有改善溶解性、改善代谢稳定性、减少非靶标毒性和12 nM Plasmodium falciparum 抗疟活性的2-吡啶基喹啉类化合物。

  DOI：

  10.1039/c5md00062a

文献信息

• [EN] ANTIMALARIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIPALUDIQUES
  申请人：LIVERPOOL SCHOOL TROPICAL MEDICINE

  公开号：WO2012069856A1

  公开（公告）日：2012-05-31

  The present invention relates to antimalarial compounds. More specifically, the present invention relates to novel substituted quinolone derivatives of formula (I) and related quinoline derivatives of formula (II) as defined herein that possess potent antimalarial activity. The present invention also relates to processes for the preparation of these quinolone and quinoline derivatives, to pharmaceutical compositions comprising them and to their use as therapeutic agents for the treatment and/or prevention of malaria.

  本发明涉及抗疟疾化合物。更具体地，本发明涉及具有强效抗疟活性的本发明中定义的新型取代喹诺酮衍生物（式（I））和相关喹啉衍生物（式（II））。本发明还涉及制备这些喹诺酮和喹啉衍生物的方法，包括含有它们的药物组合物以及它们作为治疗和/或预防疟疾的治疗剂的用途。
• Potent Antimalarial 2-Pyrazolyl Quinolone <i>bc</i>₁ (Q_i) Inhibitors with Improved Drug-like Properties
  作者：W. David Hong、Suet C. Leung、Kangsa Amporndanai、Jill Davies、Richard S. Priestley、Gemma L. Nixon、Neil G. Berry、S. Samar Hasnain、Svetlana Antonyuk、Stephen A. Ward、Giancarlo A. Biagini、Paul M. O’Neill

  DOI：10.1021/acsmedchemlett.8b00371

  日期：2018.12.13

  A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve

  已经设计并合成了一系列2-吡唑基喹诺酮类药物，分5-7个步骤进行了优化，以优化体外抗疟药功效以及各种体外药物代谢和药代动力学（DMPK）功能。与对药物敏感的菌株（3D7）相比，最有效的化合物与对多药耐药的寄生虫菌株（W2）没有交叉耐药性，IC50（达到最大最大生长抑制一半所需的药物浓度）值在15-33 nM之间。此外，该系列的成员保留了对耐阿托伐醌的寄生虫分离物（TM90C2B）的中等活性。所述的2-吡唑酰基系列显示出改善的DMPK特性，与先前报道的喹诺酮系列相比具有改善的水溶性，并且通过体外细胞毒性评估具有可接受的安全范围。
• Antituberculosis Activity of the Antimalaria Cytochrome <i>bcc</i> Oxidase Inhibitor SCR0911
  作者：Shi Min Sherilyn Chong、Malathy Sony Subramanian Manimekalai、Jickky Palmae Sarathy、Zoe C. Williams、Liam K. Harold、Gregory M. Cook、Thomas Dick、Kevin Pethe、Roderick W. Bates、Gerhard Grüber

  DOI：10.1021/acsinfecdis.9b00408

  日期：2020.4.10

  The ability to respire and generate adenosine triphosphate (ATP) is essential for the physiology, persistence, and pathogenicity of Mycobacterium tuberculosis, which causes tuberculosis. By employing a lead repurposing strategy, the malarial cytochrome bc1 inhibitor SCR0911 was tested against mycobacteria. Docking studies were carried out to reveal potential binding and to understand the binding interactions

  呼吸和产生三磷酸腺苷（ATP）的能力对于引起结核病的结核分枝杆菌的生理，持久性和致病性至关重要。通过采用铅再利用策略，对疟疾细胞色素bc1抑制剂SCR0911进行了分枝杆菌测试。进行了对接研究，以揭示潜在的结合并了解与靶标细胞色素bcc的结合相互作用。基于全细胞的体外试验证明了通过抑制快速增长和缓慢增长的耻垢分枝杆菌和牛分枝杆菌卡梅特-盖林中的细胞生长和ATP合成，SCR0911的功效。各种生化分析方法和细胞色素bcc缺陷型突变株的使用证实了细胞色素bcc氧化酶是药物的直接靶标。
• Combination of respiratory electron transport chain inhibitors with a cytochrome bd inhibitor
  申请人：Liverpool School of Tropical Medicine

  公开号：US10799494B2

  公开（公告）日：2020-10-13

  The present invention relates to a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors and a cytochrome bd inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising the combination therapeutic product and to the use of the combination therapeutic product in the treatment of mycobacterial infections, such as tuberculosis.

  本发明涉及一种包含一种或多种呼吸电子传递链抑制剂和细胞色素bd抑制剂（如本文所定义）或其药学上可接受的盐的组合治疗产品。本发明还涉及包含该组合治疗产品的药物组合物，以及该组合治疗产品在治疗结核病等分枝杆菌感染中的用途。
• Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of <i>Mycobacterium tuberculosis</i>
  作者：W. David Hong、Peter D. Gibbons、Suet C. Leung、Richard Amewu、Paul A. Stocks、Andrew Stachulski、Pedro Horta、Maria L. S. Cristiano、Alison E. Shone、Darren Moss、Alison Ardrey、Raman Sharma、Ashley J. Warman、Paul T. P. Bedingfield、Nicholas E. Fisher、Ghaith Aljayyoussi、Sally Mead、Maxine Caws、Neil G. Berry、Stephen A. Ward、Giancarlo A. Biagini、Paul M. O’Neill、Gemma L. Nixon

  DOI：10.1021/acs.jmedchem.6b01718

  日期：2017.5.11

  A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified similar to 100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further similar to 90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.