6-chloro-7-methoxy-2-methyl-3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)quinolin-4(1H)-one | 1354745-74-6

• 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-chloro-7-methoxy-2-methyl-3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)quinolin-4(1H)-one
• 英文别名: 6-chloro-7-methoxy-2-methyl-3-[4-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-1H-quinolin-4-one；6-chloro-7-methoxy-2-methyl-3-[4-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-1H-quinolin-4-one
• CAS: 1354745-74-6
• 化学式: C₂₃H₁₆ClF₃N₂O₃
• 分子量: 460.84
• InChiKey: MYVFIIUERNQKNM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  60.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-甲氧基-4-氯苯胺 在 dowtherm A 、 四(三苯基膦)钯 、 氢溴酸 、 碘 、 potassium carbonate 、 对甲苯磺酸 、 溶剂黄146 、 正丁胺 、 potassium iodide 作用下， 以 水 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 68.83h， 生成 6-chloro-7-methoxy-2-methyl-3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)quinolin-4(1H)-one
  参考文献：
  名称：

  Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

  摘要：

  The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

  DOI：

  10.1021/jm500147k

文献信息

• Discovery, Synthesis, and Optimization of Antimalarial 4(1<i>H</i>)-Quinolone-3-Diarylethers
  作者：Aaron Nilsen、Galen P. Miley、Isaac P. Forquer、Michael W. Mather、Kasiram Katneni、Yuexin Li、Sovitj Pou、April M. Pershing、Allison M. Stickles、Eileen Ryan、Jane Xu Kelly、J. Stone Doggett、Karen L. White、David J. Hinrichs、Rolf W. Winter、Susan A. Charman、Lev N. Zakharov、Ian Bathurst、Jeremy N. Burrows、Akhil B. Vaidya、Michael K. Riscoe

  DOI：10.1021/jm500147k

  日期：2014.5.8

  The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.