5-[4-(苄氧基)苄基]-2,4-嘧啶二胺 | 49873-11-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 5-[4-(苄氧基)苄基]-2,4-嘧啶二胺
• 英文名称: 5-(4-benzyloxy-benzyl)-pyrimidine-2,4-diamine
• 英文别名: 5-[(4-Benzyloxy)benzyl]-2,4-diaminopyrimidine；5-[(4-phenylmethoxyphenyl)methyl]pyrimidine-2,4-diamine
• CAS: 49873-11-2
• 化学式: C₁₈H₁₈N₄O
• 分子量: 306.367
• InChiKey: NTVMHTFWSNGDLC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P264,P280,P302+P352,P305+P351+P338,P332+P313,P337+P313,P362
• 危险性描述：
  H315,H319

反应信息

• 作为反应物：
  描述：

  5-[4-(苄氧基)苄基]-2,4-嘧啶二胺 在 palladium on activated charcoal 氢气 、 溶剂黄146 作用下， 90.0~100.0 ℃ 、310.27 kPa 条件下， 以56%的产率得到2,4-diamino-5-(4-hydroxybenzyl)pyrimidine
  参考文献：
  名称：

  2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 7. Analysis of the effect of 3,5-dialkyl substituent size and shape on binding to four different dihydrofolate reductase enzymes

  摘要：

  A group of trimethoprim (TMP) analogues containing 3,5-dialkyl(or halo)-4-alkoxy, -hydroxy, or -amino substitution were analyzed in terms of their inhibitory activities against four dihydrofolate reductase (DHFR) isozymes. Although selectivities were lower than with TMP, the activities against vertebrate DHFR were usually at least 2 orders of magnitude less than against enzymes from microbial sources. However, the profiles of activity were remarkably similar for rat, Neisseria gonorrhoeae, and Plasmodium berghei enzymes in all three series, although somewhat different for Escherichia coli DHFR, leading to the conclusion that the hydrophobic pockets are similar for the first three isozymes. Optimal substitution was reached with 3,5-di-n-propyl or 3-ethyl-5-n-propyl groups. Branching of chains at the alpha-carbon, which resulted in increased substituent thickness, was detrimental to E. coli DHFR inhibition in particular. MR is an inadequate parameter for use in correlating such substituent effects. Conformational changes of the more bulky inhibitors can be invoked to explain some differences in inhibitory pattern. Although log P explains simple substituent effects with the vertebrate DHFRs very well, it is insufficient in the more complex cases described here, where shape is clearly involved as well. Solvent-accessible surface areas were measured for TMP in E. coli and chicken DHFRs, where the coordinates are now known. The environment is more hydrophobic in the latter case; this can also be postulated for rat DHFR, which has a very similar activity profile. As with the mammalian isozymes, N. gonorrhoeae DHFR contains an active site phenylalanine replacing Leu-28 of E. coli DHFR, thus creating a more hydrophobic pocket. A similar replacement may also occur in the P.berghei isozyme. Selectivity for bacterial DHFR is dependent on the nature of the 4-substituent, being low for polar 4-hydroxy compounds but high for polar 4-amino analogues, possibly as a result of solvation differences. With complex substituents, the environment of each atom in the active site must be taken into account to adequately explain structure-activity relationships.

  DOI：

  10.1021/jm00385a017
• 作为产物：
  描述：

  4-苄氧基苯甲醛 在 盐酸 、 sodium methylate 作用下， 以 乙醇 、 二甲基亚砜 、 异丙醇 为溶剂， 反应 25.5h， 生成 5-[4-(苄氧基)苄基]-2,4-嘧啶二胺
  参考文献：
  名称：

  Hachtel; Haller; Seydel, Arzneimittel-Forschung/Drug Research, 1988, vol. 38, # 12, p. 1778 - 1783

  摘要：

  DOI：

文献信息

• 2,4-Diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase
  作者：Didier Pez、Isabel Leal、Fabio Zuccotto、Cyrille Boussard、Reto Brun、Simon L Croft、Vanessa Yardley、Luis M Ruiz Perez、Dolores Gonzalez Pacanowska、Ian H Gilbert

  DOI：10.1016/j.bmc.2003.08.012

  日期：2003.11

  selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular

  本文描述了4'-取代和3'，4'-二取代的5-苄基-2,4-二氨基嘧啶作为利什曼体和锥虫二氢叶酸还原酶的选择性抑制剂的合成。然后针对重组寄生虫和人类酶测定化合物。一些化合物显示出良好的活性。还使用体外测定法针对完整的寄生虫对它们进行了测试。发现对克鲁斯锥虫的活性良好，对布鲁氏锥虫和多形利什曼原虫的活性中等。进行分子建模以解释结果。发现利什曼酶比活性酶在活性位点具有更广泛的亲脂结合区。结合在口袋中的化合物显示出最高的选择性。
• 2,4-Diamino-5-benzylpyrimidines, especially for the treatment of microbial infections, pharmaceutical compositions containing these compounds and processes for preparing these compounds
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：EP0006987A1

  公开（公告）日：1980-01-23

  Pharmaceutical compositions containing 2,4-diamino-5-(3. 5-dialkyl-4-hydroxybenzyl) pyrimidines wherein the alkyl groups contain from 2 to 4 carbon atoms are useful in the treatment of bacterial infections. The first medical use of such compounds, novel chemical compounds wherein the alkyl groups are propyl or butyl, except the di-i-propyl compound, a process for preparing the novel compounds and chemical intermediates used in their preparation are also disclosed.

  含有 2,4-二氨基-5-(3. 5-二烷基-4-羟基苄基)嘧啶（其中烷基含有 2 至 4 个碳原子）的药物组合物可用于治疗细菌感染。此外，还公开了此类化合物的第一种医学用途、烷基为丙基或丁基的新型化合物（二丙基化合物除外）、制备新型化合物的工艺以及用于制备这些化合物的化学中间体。
• Target Guided Synthesis of 5-Benzyl-2,4-diamonopyrimidines: Their Antimalarial Activities and Binding Affinities to Wild Type and Mutant Dihydrofolate Reductases from <i>Plasmodium falciparum</i>
  作者：Chawanee Sirichaiwat、Chakapong Intaraudom、Sumalee Kamchonwongpaisan、Jarunee Vanichtanankul、Yodhathai Thebtaranonth、Yongyuth Yuthavong

  DOI：10.1021/jm0303352

  日期：2004.1.1

  The resistance to pyrimethamine (PYR) of Plasmodium falciparum arising from mutation at position 108 of dihydrofolate reductase (pfDHFR) from serine to asparagine (S108N) is due to steric interaction between the bulky side chain of N108 and Cl atom of the 5-p-Cl aryl group of PYR, which consequently resulted in the reduction in binding affinity between the enzyme and inhibitor. Molecular modeling suggested that the flexible antifolate, such as trimethoprim (TMP) derivatives, could avoid this steric constraint and should be considered as new, potentially effective compounds. The hydrophobic interaction between the side chain of inhibitor and the active site of the enzyme around position 108 was enhanced by the introduction of a longer and more hydrophobic side chain on TMP's 5-benzyl moiety. The prepared compounds, especially those bearing aromatic substituents, exhibited better binding affinities to both wild type and mutant enzymes than the parent compound. Binding affinities of these compounds correlated well with their antimalarial. activities against both wild type and resistant parasites. Molecular modeling of the binding of such compounds with pfDHFR also supported the experimental data and clearly showed that aromatic substituents play an important role in enhancing binding affinity. In addition, some compounds with 6-alkyl substituents showed relatively less decrease in binding constants with the mutant enzymes and relatively good antimalarial. activities against the parasites bearing the mutant enzymes.
• HACHTEL, G.;HALLER, R.;SEYDEL, J. K., ARZNEIM.-FORSCH., 38,(1988) N2, C. 1778-1783
  作者：HACHTEL, G.、HALLER, R.、SEYDEL, J. K.

  DOI：——

  日期：——
• FANG, ZHAO-XIA;LI, REN-LI;XU, YAN, IYAO GUNE , 19,(1988) N, S. 346-350
  作者：FANG, ZHAO-XIA、LI, REN-LI、XU, YAN

  DOI：——

  日期：——