5-Phenethyl-quinazoline-2,4-diamine | 123242-02-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 5-Phenethyl-quinazoline-2,4-diamine
• 英文别名: 5-Phenethylquinazoline-2,4-diamine；5-(2-phenylethyl)quinazoline-2,4-diamine
• CAS: 123242-02-4
• 化学式: C₁₆H₁₆N₄
• 分子量: 264.33
• InChiKey: UIHMRPRVKDDARV-UHFFFAOYSA-N

物化性质

• 沸点：
  516.3±42.0 °C(Predicted)
• 密度：
  1.270±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,6-二硝基氯苯 在 palladium on activated charcoal 盐酸 、 copper(l) iodide 、 硫酸 、 氢气 、 palladium diacetate 、 铁粉 、 三(邻甲基苯基)磷 、 potassium iodide 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 二乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 25.0~150.0 ℃ 、101.33 kPa 条件下， 反应 9.0h， 生成 5-Phenethyl-quinazoline-2,4-diamine
  参考文献：
  名称：

  5-取代的2,4-二氨基喹唑啉的抗叶酸和抗菌活性。

  摘要：

  合成了一系列5-取代的2,4-二氨基喹唑啉（3），并从细菌和哺乳动物来源评估了它们作为二氢叶酸还原酶（DHFR）的抑制剂。最好的化合物（例如53种）对大肠杆菌DHFR表现出良好的活性，但对细菌的选择性没有比哺乳动物酶高的选择性。抑制酶的构效关系似乎很复杂，不宜进行简单分析。提出了一个假设来解释观察到的定性结构-活性关系。该化合物对体外完整细菌细胞生长的抑制活性与抑制分离的细菌酶的抑制活性非常相似，这表明它们的抗叶酸作用是其抗菌作用的原因。

  DOI：

  10.1021/jm00163a067

文献信息

• Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of <i>Cryptosporidium parvum</i> Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations
  作者：Richard G. Nelson、Andre Rosowsky

  DOI：10.1128/aac.45.12.3293-3303.2001

  日期：2001.12

  A structurally diverse library of 93 lipophilic di- and tricyclic diaminopyrimidine derivatives was tested for the ability to inhibit recombinant dihydrofolate reductase (DHFR) cloned from human and bovine isolates of Cryptosporidium parvum (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153–165, 1996). In parallel, the library was also tested against human DHFR and, for comparison, the enzyme from Escherichia coli . Fifty percent inhibitory concentrations (IC ₅₀ s) were determined by means of a standard spectrophotometric assay of DHFR activity with dihydrofolate and NADPH as the cosubstrates. Of the compounds tested, 25 had IC ₅₀ s in the 1 to 10 μM range against one or both C. parvum enzymes and thus were not substantially different from trimethoprim (IC ₅₀ s, ca. 4 μM). Another 25 compounds had IC ₅₀ s of <1.0 μM, and 9 of these had IC ₅₀ s of <0.1 μM and thus were at least 40 times more potent than trimethoprim. The remaining 42 compounds were weak inhibitors (IC ₅₀ s, >10 μM) and thus were not considered to be of interest as drugs useful against this organism. A good correlation was generally obtained between the results of the spectrophotometric enzyme inhibition assays and those obtained recently in a yeast complementation assay (V. H. Brophy et al., Antimicrob. Agents Chemother. 44:1019–1028, 2000; H. Lau et al., Antimicrob. Agents Chemother. 45:187–195, 2001). Although many of the compounds in the library were more potent than trimethoprim, none had the degree of selectivity of trimethoprim for C. parvum versus human DHFR. Collectively, the results of these assays comprise the largest available database of lipophilic antifolates as potential anticryptosporidial agents. The compounds in the library were also tested as inhibitors of the proliferation of intracellular C. parvum oocysts in canine kidney epithelial cells cultured in folate-free medium containing thymidine (10 μM) and hypoxanthine (100 μM). After 72 h of drug exposure, the number of parasites inside the cells was quantitated by indirect immunofluorescence microscopy. Sixteen compounds had IC ₅₀ s of <3 μM, and five of these had IC ₅₀ s of <0.3 μM and thus were comparable in potency to trimetrexate. The finding that submicromolar concentrations of several of the compounds in the library could inhibit in vitro growth of C. parvum in host cells in the presence of thymidine (dThd) and hypoxanthine (Hx) suggests that lipophilic DHFR inhibitors, in combination with leucovorin, may find use in the treatment of intractable C. parvum infections.

  摘要 对 93 种亲脂性二环和三环二氨基嘧啶衍生物的结构多样性文库进行了测试，以检测其抑制从人和牛分离的副隐孢子虫中克隆的重组二氢叶酸还原酶（DHFR）的能力。 副猪隐孢子虫 (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153-165, 1996)。与此同时，该文库还针对人类 DHFR 进行了测试，并与来自 大肠杆菌 .五成抑制浓度（IC 50 s）是通过以二氢叶酸和 NADPH 为共底物的 DHFR 活性标准分光光度法测定的。在测试的化合物中，25 个化合物的 IC 50 在 1 至 10 μM 范围内，对一种或两种 C. parvum 因此与三甲氧苄啶（IC 50 s，约为 4 μM）没有本质区别。另外 25 种化合物的 IC 50 s 为 1.0 μM，其中 9 种化合物的 IC 50 为 0.1 μM，因此药效至少是三甲氧苄啶的 40 倍。其余 42 种化合物为弱抑制剂（IC 50 s，>10 μM），因此不被认为是对这种生物有用的药物。分光光度法酶抑制测定的结果与最近在酵母互补测定中获得的结果之间通常具有良好的相关性（V. H. Brophy 等人，Antimicrob.Agents Chemother.44:1019-1028, 2000; H. Lau et al.Agents Chemother.45:187-195, 2001).虽然文库中的许多化合物都比三甲氧苄氨嘧啶更有效，但没有一种化合物具有三甲氧苄氨嘧啶对副猪嗜血杆菌的选择性。 副猪嗜血杆菌 对人类 DHFR 的选择性。总之，这些检测结果构成了目前最大的亲脂性抗酚化合物潜在抗隐孢子虫药物数据库。该化合物库中的化合物还作为细胞内副猪嗜血杆菌增殖抑制剂进行了测试。 副猪嗜血杆菌 卵囊在含有胸苷（10 μM）和次黄嘌呤（100 μM）的无叶酸培养基中培养的犬肾上皮细胞中的增殖抑制剂。药物暴露 72 小时后，通过间接免疫荧光显微镜对细胞内的寄生虫数量进行量化。16种化合物的IC 50 为 <3 μM，其中五个化合物的 IC 50 s 为 <0.3 μM，因此其效力与三甲曲沙相当。研究发现，库中几种亚摩尔浓度的化合物可抑制副嗜血杆菌的体外生长。 副猪嗜血杆菌 在胸苷（dThd）和次黄嘌呤（Hx）存在的宿主细胞中的体外生长。 C. parvum 感染。
• Antifolate and antibacterial activities of 5-substituted 2,4-diaminoquinazolines
  作者：Neil V. Harris、Christopher Smith、Keith Bowden

  DOI：10.1021/jm00163a067

  日期：1990.1

  observed qualitative structure-activity relationships is proposed. The inhibitory activities of the compounds against the growth of intact bacterial cells in vitro closely parallel those for the inhibition of the isolated bacterial enzymes, suggesting that their antifolate action is responsible for their antibacterial effects. Five of the compounds were tested for their ability to cure a systemic E

  合成了一系列5-取代的2,4-二氨基喹唑啉（3），并从细菌和哺乳动物来源评估了它们作为二氢叶酸还原酶（DHFR）的抑制剂。最好的化合物（例如53种）对大肠杆菌DHFR表现出良好的活性，但对细菌的选择性没有比哺乳动物酶高的选择性。抑制酶的构效关系似乎很复杂，不宜进行简单分析。提出了一个假设来解释观察到的定性结构-活性关系。该化合物对体外完整细菌细胞生长的抑制活性与抑制分离的细菌酶的抑制活性非常相似，这表明它们的抗叶酸作用是其抗菌作用的原因。