2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline | 1361968-62-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline
• 英文别名: 2-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-5-fluoroaniline
• CAS: 1361968-62-8
• 化学式: C₁₁H₁₃FN₂O
• 分子量: 208.235
• InChiKey: PCKZJCWTEYKKQS-UHFFFAOYSA-N

物化性质

• 沸点：
  319.2±32.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  法尼基丙酮 、 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline 在 对甲苯磺酸 作用下， 以 正丁醇 为溶剂， 反应 24.0h， 以26%的产率得到7-fluoro-2-methyl-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)quinolin-4(1H)-one
  参考文献：
  名称：

  Aurachin D 类似物作为结核分枝杆菌细胞色素 bd 氧化酶抑制剂的合成及生物学评价

  摘要：

  aurachin D ( 1a ) 是一种类异戊二烯喹诺酮生物碱，靶向结核分枝杆菌( Mtb ) 细胞色素bd (cyt- bd ) 氧化酶，使用恶唑啉开环反应完成了修订的全合成。开环使得能够获得一系列贫电子类似物，而富电子类似物可以使用康拉德-林帕奇反应来制备。筛选了芳基取代和侧链修饰的金豆素 D 类似物，以抑制Mtb细胞色素-bd氧化酶和抑制Mtb生长。观察到短链类似物1d（香茅基侧链）和芳基取代类似物1g / 1k（C6/C7 处的氟取代基）、1t / 1v（C5/C6 处的羟基取代基）对Mtb cyt - bd氧化酶的纳摩尔抑制) 和1u / 1w / 1x (C5/C6/C7 处的甲氧基取代基)。Aurachin D 及其类似物不会抑制非致病性耻垢分枝杆菌的生长，但Mtb cyt -bd氧化酶测定中的香茅基 ( 1d ) 和 6-氟取代 ( 1g ) 抑制剂对致病性Mtb表现出中等的生长抑制作用(MIC

  DOI：

  10.1021/acsmedchemlett.2c00401
• 作为产物：
  描述：

  2-氨基-4-氟苯甲酸 在 potassium carbonate 、 zinc(II) chloride 作用下， 以 乙酸乙酯 、 氯苯 为溶剂， 反应 42.0h， 生成 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluoroaniline
  参考文献：
  名称：

  恶性疟原虫（Pf NDH2）与小分子的NADH-泛醌氧化还原酶共晶体结构的目标阐明，以消除抗药性疟疾。

  摘要：

  最近，耐药性疟疾菌株不断出现，这对全球健康构成了巨大挑战。因此，迫切需要具有新颖靶向机制的新抗疟药来对抗耐药性疟疾。恶性疟原虫的NADH-泛醌氧化还原酶（Pf NDH2）代表了抗疟疾药物开发的可行目标。但是，缺乏有关Pf NDH2的结构信息限制了合理的药物设计和进一步的开发。在这里，我们首次报道了Af-，NADH-和RYL-552（一种新的抑制剂）结合状态的Pf NDH2蛋白的高分辨率晶体结构。该Pf的NDH2抑制剂通过潜在的变构机制，对体外耐药菌和体内寄生虫感染的小鼠均表现出出色的效力。此外，发现该抑制剂可以与二氢青蒿素（DHA）协同地结合使用。这些发现不仅对于基于疟疾Pf NDH2蛋白的药物开发很重要，而且对其他含有NDH2的致病微生物（如结核分枝杆菌）也可能具有广泛的意义。

  DOI：

  10.1021/acs.jmedchem.6b01733

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。
• 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.
• Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
  作者：Suet C. Leung、Peter Gibbons、Richard Amewu、Gemma L. Nixon、Chandrakala Pidathala、W. David Hong、Bénédicte Pacorel、Neil G. Berry、Raman Sharma、Paul A. Stocks、Abhishek Srivastava、Alison E. Shone、Sitthivut Charoensutthivarakul、Lee Taylor、Olivier Berger、Alison Mbekeani、Alasdair Hill、Nicholas E. Fisher、Ashley J. Warman、Giancarlo A. Biagini、Stephen A. Ward、Paul M. O’Neill

  DOI：10.1021/jm201184h

  日期：2012.3.8

  Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC50 = 15 nM PfNDH2; IC50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED50/ED90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.