6-Ethyl-5-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4-diamine | 656810-05-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 6-Ethyl-5-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4-diamine
• 英文别名: 6-Ethyl-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
• CAS: 656810-05-8
• 化学式: C₁₆H₂₂N₄O₃
• 分子量: 318.376
• InChiKey: DEHBKCBJXJWRAZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3,4,5-三甲氧基苯甲醛 在 sodium methylate 作用下， 以 1,4-二氧六环 、 乙醇 、 二甲基亚砜 为溶剂， 生成 6-Ethyl-5-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4-diamine
  参考文献：
  名称：

  Target Guided Synthesis of 5-Benzyl-2,4-diamonopyrimidines: Their Antimalarial Activities and Binding Affinities to Wild Type and Mutant Dihydrofolate Reductases from Plasmodium falciparum

  摘要：

  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.

  DOI：

  10.1021/jm0303352

文献信息

• 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.