4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline

• 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: 4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline
• 英文别名: 2-(2'-amino-5'-chlorophenyl)-4,4-dimethyl-2-oxazoline；4-chloro-2-(4,4-dimethyl-5H-1,3-oxazol-2-yl)aniline
• 化学式: C₁₁H₁₃ClN₂O
• 分子量: 224.69
• InChiKey: HQELTNNLKKSHMH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 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：
  3

反应信息

• 作为反应物：
  描述：

  1-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)propan-1-one 、 4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline 在 对甲苯磺酸 作用下， 以 正丁醇 为溶剂， 反应 24.0h， 以34%的产率得到6-chloro-3-methyl-2-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)quinolin-4(1H)-one
  参考文献：
  名称：

  Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

  摘要：

  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.

  DOI：

  10.1021/jm201184h
• 作为产物：
  描述：

  5-氯靛红酸酐 、 2-氨基-2-甲基-1-丙醇 在 zinc(II) chloride 作用下， 以 氯苯 为溶剂， 以77%的产率得到4-chloro-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline
  参考文献：
  名称：

  恶唑啉化学部分III。[2-（2'-苯胺基）-2-恶唑啉]及一些相关化合物的合成与表征

  摘要：

  报道了一系列手性和非手性2-（氨基苯基）-2-恶唑啉及一些相关化合物的合成与表征。所有衍生物均是通过一步法生产的，其中涉及对等酸酐的处理（即[2 H ] -3、1-苯并恶嗪-[1 H -2,4-二酮：1 ]或其5-氯类似物并略有过量的适当氨基醇。在大多数情况下，在高沸点芳烃溶剂（PhCl或PhMe）中，在回流温度下，无水ZnCl 2被证明是该反应的有效路易斯酸催化剂。使用rac -2-氨基-1-丁醇，（S）-苯基甘醇，2-甲基-2-氨基-1-丙醇和（1S，2R）或（1R，2S） -顺式- 1 -氨基-2-茚满醇; 收率从85％到22％。使用氨基醇，例如2-乙醇胺，（±）-2-氨基-1-苯基-1-丙醇或3-氨基-1-丙醇（得到相应的4,5-二氢-1,3-恶嗪）导致产量不佳。使用其他路易斯酸催化剂（硅酸，Cd（acac）2 ·2H 2 O，CuCl 2 ·2H 2 O，InCl 3）或更高的温

  DOI：

  10.1002/jhet.5570400316

文献信息

• 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。
• Oxazoline chemistry part III. Synthesis and characterisation of [2-(2′-anilinyl)-2-oxazolines] and some related compounds
  作者：Karen M. Button、Robert A. Gossage

  DOI：10.1002/jhet.5570400316

  日期：2003.5

  The syntheses and characterisation of a series of chiral and achiral 2-(aminophenyl)-2-oxazolines and some related compounds is reported. All of the derivatives have been produced by a one-step procedure involving the treatment of isatoic anhydride (i.e. [2H]-3, 1-benzoxazine-[1H-2,4-dione: 1) or its 5-chloro analogue with a slight excess of appropriate amino-alcohols. In most cases, anhydrous ZnCl2

  报道了一系列手性和非手性2-（氨基苯基）-2-恶唑啉及一些相关化合物的合成与表征。所有衍生物均是通过一步法生产的，其中涉及对等酸酐的处理（即[2 H ] -3、1-苯并恶嗪-[1 H -2,4-二酮：1 ]或其5-氯类似物并略有过量的适当氨基醇。在大多数情况下，在高沸点芳烃溶剂（PhCl或PhMe）中，在回流温度下，无水ZnCl 2被证明是该反应的有效路易斯酸催化剂。使用rac -2-氨基-1-丁醇，（S）-苯基甘醇，2-甲基-2-氨基-1-丙醇和（1S，2R）或（1R，2S） -顺式- 1 -氨基-2-茚满醇; 收率从85％到22％。使用氨基醇，例如2-乙醇胺，（±）-2-氨基-1-苯基-1-丙醇或3-氨基-1-丙醇（得到相应的4,5-二氢-1,3-恶嗪）导致产量不佳。使用其他路易斯酸催化剂（硅酸，Cd（acac）2 ·2H 2 O，CuCl 2 ·2H 2 O，InCl 3）或更高的温
• Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of <i>Mycobacterium tuberculosis</i> Cytochrome <i>bd</i> Oxidase
  作者：Aggie Lawer、Chelsea Tyler、Kiel Hards、Laura M. Keighley、Chen-Yi Cheung、Fabian Kierek、Simon Su、Siddharth S. Matikonda、Tyler McInnes、Joel D. A. Tyndall、Kurt L. Krause、Gregory M. Cook、Allan B. Gamble

  DOI：10.1021/acsmedchemlett.2c00401

  日期：2022.10.13

  A revised total synthesis of aurachin D (1a), an isoprenoid quinolone alkaloid that targets Mycobacterium tuberculosis (Mtb) cytochrome bd (cyt-bd) oxidase, was accomplished using an oxazoline ring-opening reaction. The ring opening enabled access to a range of electron-poor analogues, while electron-rich analogues could be prepared using the Conrad–Limpach reaction. The aryl-substituted and side-chain-modified

  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
• Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
  作者：Chandrakala Pidathala、Richard Amewu、Bénédicte Pacorel、Gemma L. Nixon、Peter Gibbons、W. David Hong、Suet C. Leung、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/jm201179h

  日期：2012.3.8

  the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates

  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
• 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.