4,6-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide | 1473450-25-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4,6-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide
• 英文别名: 4,6-dimethyl-N-tetrahydropyran-4-yl-1H-indole-2-carboxamide；4,6-dimethyl-N-(oxan-4-yl)-1H-indole-2-carboxamide
• CAS: 1473450-25-7
• 化学式: C₁₆H₂₀N₂O₂
• 分子量: 272.347
• InChiKey: OUQDYLLHFXVOBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  4-氨基四氢吡喃 、 4,6-二甲基-1H-吲哚-2-羧酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.17h， 以70%的产率得到4,6-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides: A Promising Class of Antituberculosis Agents

  摘要：

  Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluor, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.

  DOI：

  10.1021/jm4012774

文献信息

• Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides: A Promising Class of Antituberculosis Agents
  作者：Ravinder Reddy Kondreddi、Jan Jiricek、Srinivasa P. S. Rao、Suresh B. Lakshminarayana、Luis R. Camacho、Ranga Rao、Maxime Herve、Pablo Bifani、Ngai Ling Ma、Kelli Kuhen、Anne Goh、Arnab K. Chatterjee、Thomas Dick、Thierry T. Diagana、Ujjini H. Manjunatha、Paul W. Smith

  DOI：10.1021/jm4012774

  日期：2013.11.14

  Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluor, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.