N⁴-(3-(benzo[b]thiophen-2-yl)-5-chlorophenyl)-6-methylpyrimidine-2,4-diamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: N⁴-(3-(benzo[b]thiophen-2-yl)-5-chlorophenyl)-6-methylpyrimidine-2,4-diamine
• 英文别名: UTSAM601；4-N-[3-(1-benzothiophen-2-yl)-5-chlorophenyl]-6-methylpyrimidine-2,4-diamine
• 化学式: C₁₉H₁₅ClN₄S
• 分子量: 366.874
• InChiKey: BHHHJZPZQFREGK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  92.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氨基-4-氯-6-甲基嘧啶 在 盐酸 、 Sodium tripolyphosphate 、 水 、 palladium diacetate 、 三苯基膦 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 19.5h， 生成 N⁴-(3-(benzo[b]thiophen-2-yl)-5-chlorophenyl)-6-methylpyrimidine-2,4-diamine
  参考文献：
  名称：

  Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase

  摘要：

  New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.

  DOI：

  10.1021/acs.jmedchem.7b01654