3‐methyl-2-(4‐(1-(2-morpholinoethyl)-1H‐pyrazol‐4-yl)phenyl)quinolin‐4(1H)‐one | 1361968-20-8

• 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: 3‐methyl-2-(4‐(1-(2-morpholinoethyl)-1H‐pyrazol‐4-yl)phenyl)quinolin‐4(1H)‐one
• 英文别名: 3-methyl-2-[4-[1-(2-morpholinoethyl)pyrazol-4-yl]phenyl]-1H-quinolin-4-one；3-methyl-2-[4-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]phenyl]-1H-quinolin-4-one
• CAS: 1361968-20-8
• 化学式: C₂₅H₂₆N₄O₂
• 分子量: 414.507
• InChiKey: BPVFCGQLRYFYEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  59.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-羟基苯丙酮 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 对甲苯磺酸 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 正丁醇 为溶剂， 反应 40.0h， 生成 3‐methyl-2-(4‐(1-(2-morpholinoethyl)-1H‐pyrazol‐4-yl)phenyl)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

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。
• 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.