2,4-Diamino-5-α-methylnaphthyl-pyrimidin | 93734-31-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2,4-Diamino-5-α-methylnaphthyl-pyrimidin
• 英文别名: 5-naphthalen-1-ylmethyl-pyrimidine-2,4-diamine；5-(Naphthalen-1-ylmethyl)pyrimidine-2,4-diamine
• CAS: 93734-31-7
• 化学式: C₁₅H₁₄N₄
• 分子量: 250.303
• InChiKey: HKCKBLDMOOFVQE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 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：

  在 盐酸 、 sodium methylate 作用下， 以 乙醇 、 异丙醇 为溶剂， 反应 36.0h， 生成 2,4-Diamino-5-α-methylnaphthyl-pyrimidin
  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

• Immobilization of Malarial (<i>Plasmodium falciparum</i>) Dihydrofolate Reductase for the Selection of Tight-Binding Inhibitors from Combinatorial Library
  作者：Chawanee Thongpanchang、Supannee Taweechai、Sumalee Kamchonwongpaisan、Yongyuth Yuthavong、Yodhathai Thebtaranonth

  DOI：10.1021/ac070215s

  日期：2007.7.1

  A simple procedure for selection of tight-binding inhibitors of mutant dihydrofolate reductases from Plasmodium falciparum (PfDHFRs) based on preferential binding to the enzyme immobilized on a Sepharose column has been described. PfDHFRs with a cysteine residue at the C-terminal have been prepared in order to immobilize to a thiopropyl-Sepharose gel via S−S linkage. The amount of immobilized DHFRs was estimated to be 4−5 mg/g of dried gel, and the activities of bound DHFRs were comparable to that of free enzymes. The prepared immobilized enzyme has been used for the selection of tight-binding inhibitors from combinatorial libraries, based on the affinities of each ligand with the enzyme. Free ligands were then identified and analyzed quantitatively by high-performance liquid chromatography−mass spectrometry, and the components with high binding affinity of the library could thus be realized. Results could be confirmed by quantitative analysis of the bound ligands released from the enzyme by guanidine hydrochloride treatment.

  已经描述了一种基于优先结合固定在Sepharose柱上的酶的选择突变型恶性疟原虫二氢叶酸还原酶（PfDHFRs）的紧密结合抑制剂的简单程序。为了通过S-S键固定到硫丙基-Sepharose凝胶上，制备了在C末端具有半胱氨酸残基的PfDHFRs。估计固定化的DHFRs量为4-5毫克/克干燥凝胶，并且与自由酶的活性相当。制备的固定化酶已被用于从组合库中选择紧密结合抑制剂，基于每个配体与酶的亲和力。然后通过高效液相色谱-质谱法识别和定量分析自由配体，从而实现库中具有高结合亲和力的成分。结果可以通过定量分析通过盐酸胍处理从酶中释放的结合配体来确认。
• Substituted pyrimidines, their synthesis and compositions containing them, their use in medicine and intermediates for making them
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：EP0051879A2

  公开（公告）日：1982-05-19

  Compounds of the formula (1): or a salt, N-oxide or acyl derivative thereof, wherein is a six membered ring optionally containing a hetero atom double bonds, both the phenyl ring and the being optionally substituted except that when does not contain a hetero atom either or both the phenyl ring or must be substituted other than solely by a hydroxy group at the 4-position of the phenyl ring, and that there are no substituents attached to the atom of adjacent to the 6-position of the phenyl ring are useful in the treatment of bacterial infections. A process for preparing these compounds and novel chemical intermediates used in their preparation are disclosed as is the first medical use of the compounds of the formula (I) and pharmaceutical compositions containing them.

  式(1)化合物： 或其盐、N-氧化物或酰基衍生物，其中苯基环和苯基环均可被任选取代，但当不含有杂原子时，苯基环或苯基环均必须被取代，而不是仅被苯基环 4 位上的羟基取代，且与苯基环 6 位相邻的原子上不连接任何取代基。 本发明公开了制备这些化合物的工艺和用于制备这些化合物的新型化学中间体，以及式（I）化合物和含有这些化合物的药物组合物的首次医学用途。
• US4438267A
  申请人：——

  公开号：US4438267A

  公开（公告）日：1984-03-20
• US4603136A
  申请人：——

  公开号：US4603136A

  公开（公告）日：1986-07-29
• 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.