甲基3-氰基-1-甲基-1H-吡唑-5-羧酸酯 | 232281-30-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 甲基3-氰基-1-甲基-1H-吡唑-5-羧酸酯
• 中文别名: 3-氰基-1-甲基-5-吡唑甲酸甲酯
• 英文名称: methyl 3-cyano-1-methyl-1H-pyrazole-5-carboxylate
• 英文别名: methyl 5-cyano-2-methylpyrazole-3-carboxylate
• CAS: 232281-30-0
• 化学式: C₇H₇N₃O₂
• 分子量: 165.151
• InChiKey: OVXHGMMTZKIPQR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  67.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  甲基3-氰基-1-甲基-1H-吡唑-5-羧酸酯 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 以37%的产率得到3-cyano-1-methyl-1H-pyrazole-5-carboxylic acid
  参考文献：
  名称：

  Optimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber’s Pole Worm

  摘要：

  A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 mu M. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 mu M. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 mu M.

  DOI：

  10.1021/acs.jmedchem.8b01544
• 作为产物：
  描述：

  3,5-吡唑二甲酸 在 氯化亚砜 、 硫酸 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸酐 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 51.0h， 生成 甲基3-氰基-1-甲基-1H-吡唑-5-羧酸酯
  参考文献：
  名称：

  Optimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber’s Pole Worm

  摘要：

  A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 mu M. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 mu M. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 mu M.

  DOI：

  10.1021/acs.jmedchem.8b01544

文献信息

• US6740647B1
  申请人：——

  公开号：US6740647B1

  公开（公告）日：2004-05-25
• Structure–Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of<i>Haemonchus contortus</i>Development
  作者：Thuy G. Le、Abhijit Kundu、Atanu Ghoshal、Nghi H. Nguyen、Sarah Preston、Yaqing Jiao、Banfeng Ruan、Lian Xue、Fei Huang、Jennifer Keiser、Andreas Hofmann、Bill C. H. Chang、Jose Garcia-Bustos、Timothy N. C. Wells、Michael J. Palmer、Abdul Jabbar、Robin B. Gasser、Jonathan B. Baell

  DOI：10.1021/acs.jmedchem.8b01789

  日期：2019.1.24

  Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 mu M while displaying good selectivity, with an IC50 of 37.9 mu M for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
• Optimization of Novel 1-Methyl-1<i>H</i>-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber’s Pole Worm
  作者：Thuy G. Le、Abhijit Kundu、Atanu Ghoshal、Nghi H. Nguyen、Sarah Preston、Yaqing Jiao、Banfeng Ruan、Lian Xue、Fei Huang、Jennifer Keiser、Andreas Hofmann、Bill C. H. Chang、Jose Garcia-Bustos、Abdul Jabbar、Timothy N. C. Wells、Michael J. Palmer、Robin B. Gasser、Jonathan B. Baell

  DOI：10.1021/acs.jmedchem.8b01544

  日期：2018.12.13

  A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 mu M. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 mu M. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 mu M.