pyridine-2-sulfonic acid (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amide | 851758-65-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: pyridine-2-sulfonic acid (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amide
• 英文别名: N-(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)pyridine-2-sulfonamide
• CAS: 851758-65-1
• 化学式: C₁₅H₁₄N₄O₂S
• 分子量: 314.368
• InChiKey: RDTNDJSVCVEJPE-UHFFFAOYSA-N

物化性质

• 沸点：
  571.9±60.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  pyridine-2-sulfonic acid (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amide 在 caesium carbonate 、 三氟乙酸 作用下， 以 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.0h， 生成 Pyridine-2-sulfonic acid [6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-pyridin-2-ylmethyl-amide
  参考文献：
  名称：

  Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

  摘要：

  New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THQ PFTIs with antimalaria activity.

  DOI：

  10.1021/jm0491039
• 作为产物：
  描述：

  (6-Bromo-1,2,3,4-tetrahydro-3-quinolinyl)carbamic acid, 1,1-dimethylethyl ester 在 四(三苯基膦)钯 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 pyridine-2-sulfonic acid (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amide
  参考文献：
  名称：

  Design, synthesis, and structure–activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors

  摘要：

  Tetrahydroquinoline-based small molecule inhibitors of farnesyltransferase (FT) have been identified. Lead compounds were shown to have nanomolar to sub-nanomolar activity in biochemical assays with excellent potency in a Ras-mutated cellular reversion assay. BMS-316810 (9e), a 0.7 nM FT inhibitor, was orally-active in a nude mouse tumor allograft efficacy study. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.02.004

文献信息

• Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors as Antimalarials
  作者：Pravin Bendale、Srinivas Olepu、Praveen Kumar Suryadevara、Vivek Bulbule、Kasey Rivas、Laxman Nallan、Brian Smart、Kohei Yokoyama、Sudha Ankala、Prakash Rao Pendyala、David Floyd、Louis J. Lombardo、David K. Williams、Frederick S. Buckner、Debopam Chakrabarti、Christophe L. M. J. Verlinde、Wesley C. Van Voorhis、Michael H. Gelb

  DOI：10.1021/jm0703340

  日期：2007.9.1

  Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the lownanomolar ran-e. This body of structure- activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.
• Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity
  作者：Laxman Nallan、Kevin D. Bauer、Pravin Bendale、Kasey Rivas、Kohei Yokoyama、Carolyn P. Hornéy、Prakash Rao Pendyala、David Floyd、Louis J. Lombardo、David K. Williams、Andrew Hamilton、Said Sebti、William T. Windsor、Patricia C. Weber、Frederick S. Buckner、Debopam Chakrabarti、Michael H. Gelb、Wesley C. Van Voorhis

  DOI：10.1021/jm0491039

  日期：2005.6.1

  New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THQ PFTIs with antimalaria activity.
• Design, synthesis, and structure–activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors
  作者：Louis J. Lombardo、Amy Camuso、John Clark、Krista Fager、Johnni Gullo-Brown、John T. Hunt、Ivan Inigo、David Kan、Barry Koplowitz、Francis Lee、Kelly McGlinchey、Ligang Qian、Carolyn Ricca、George Rovnyak、Sarah Traeger、John Tokarski、David K. Williams、Laurence I. Wu、Yufen Zhao、Veeraswamy Manne、Rajeev S. Bhide

  DOI：10.1016/j.bmcl.2005.02.004

  日期：2005.4

  Tetrahydroquinoline-based small molecule inhibitors of farnesyltransferase (FT) have been identified. Lead compounds were shown to have nanomolar to sub-nanomolar activity in biochemical assays with excellent potency in a Ras-mutated cellular reversion assay. BMS-316810 (9e), a 0.7 nM FT inhibitor, was orally-active in a nude mouse tumor allograft efficacy study. (c) 2005 Elsevier Ltd. All rights reserved.