2-[4-[4-[(2,4-Diaminopyrimidin-5-yl)oxymethyl]phenoxy]butyl]isoindoline-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-[4-[4-[(2,4-Diaminopyrimidin-5-yl)oxymethyl]phenoxy]butyl]isoindoline-1,3-dione
• 英文别名: 2-[4-[4-[(2,4-diaminopyrimidin-5-yl)oxymethyl]phenoxy]butyl]isoindole-1,3-dione
• 化学式: C₂₃H₂₃N₅O₄
• 分子量: 433.467
• InChiKey: FQBOXGPZSPTXDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-[4-(4-Methylphenoxy)butyl]isoindole-1,3-dione 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 sodium ethanolate 作用下， 以 四氯化碳 、 乙醇 为溶剂， 生成 2-[4-[4-[(2,4-Diaminopyrimidin-5-yl)oxymethyl]phenoxy]butyl]isoindoline-1,3-dione
  参考文献：
  名称：

  Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against Candida albicansSynthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4‘-Substituted 4-Aminodiphenyl Sulfones

  摘要：

  The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I-50 values compared to those obtained previously against Plasmodium berghei- and E. coli-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I-50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.

  DOI：

  10.1021/jm030931w

文献信息

• Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against <i>Candida </i><i>a</i><i>lbicans</i>Synthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4‘-Substituted 4-Aminodiphenyl Sulfones
  作者：Thomas Otzen、Ellen G. Wempe、Brigitte Kunz、Rainer Bartels、Gudrun Lehwark-Yvetot、Wolfram Hänsel、Klaus-Jürgen Schaper、Joachim K. Seydel

  DOI：10.1021/jm030931w

  日期：2004.1.1

  The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I-50 values compared to those obtained previously against Plasmodium berghei- and E. coli-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I-50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.