N-(4-((ethylamino)methyl)-3-hydroxyphenyl)acetamide | 620627-81-8

• 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: N-(4-((ethylamino)methyl)-3-hydroxyphenyl)acetamide
• 英文别名: N-[4-(ethylaminomethyl)-3-hydroxyphenyl]acetamide
• CAS: 620627-81-8
• 化学式: C₁₁H₁₆N₂O₂
• 分子量: 208.26
• InChiKey: UHUTYXKKDZZYIX-UHFFFAOYSA-N

物化性质

• 沸点：
  413.1±40.0 °C(Predicted)
• 密度：
  1.162±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  61.4
• 氢给体数：
  3
• 氢受体数：
  3

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  N-(3-羟基苯基)乙酰胺	3-Hydroxyacetanilid	621-42-1	C8H9NO2	151.165

反应信息

• 作为反应物：
  描述：

  N-(4-((ethylamino)methyl)-3-hydroxyphenyl)acetamide 在 盐酸 、 水 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 N-(4-((ethylamino)methyl)-3-hydroxyphenyl)-7-chloro-4-aminoquinoline
  参考文献：
  名称：

  Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents

  摘要：

  The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against Plasmodium berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.

  DOI：

  10.1021/jm300831b
• 作为产物：
  描述：

  聚合甲醛 、 乙胺 、 N-(3-羟基苯基)乙酰胺 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 24.0h， 以55%的产率得到N-(4-((ethylamino)methyl)-3-hydroxyphenyl)acetamide
  参考文献：
  名称：

  Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents

  摘要：

  The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against Plasmodium berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.

  DOI：

  10.1021/jm300831b

文献信息

• Isoquine and Related Amodiaquine Analogues:  A New Generation of Improved 4-Aminoquinoline Antimalarials
  作者：Paul M. O'Neill、Amira Mukhtar、Paul A. Stocks、Laura E. Randle、Stephen Hindley、Stephen A. Ward、Richard C. Storr、Jamie F. Bickley、Ian A. O'Neil、James L. Maggs、Ruth H. Hughes、Peter A. Winstanley、Patrick G. Bray、B. Kevin Park

  DOI：10.1021/jm030796n

  日期：2003.11.1

  Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
• Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents
  作者：Sandra Gemma、Caterina Camodeca、Margherita Brindisi、Simone Brogi、Gagan Kukreja、Sanil Kunjir、Emanuele Gabellieri、Leonardo Lucantoni、Annette Habluetzel、Donatella Taramelli、Nicoletta Basilico、Roberta Gualdani、Francesco Tadini-Buoninsegni、Gianluca Bartolommei、Maria Rosa Moncelli、Rowena E. Martin、Robert L. Summers、Stefania Lamponi、Luisa Savini、Isabella Fiorini、Massimo Valoti、Ettore Novellino、Giuseppe Campiani、Stefania Butini

  DOI：10.1021/jm300831b

  日期：2012.12.13

  The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against Plasmodium berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.