2-[(4-羟基-2-喹唑啉基)硫基]丙酸 | 328977-86-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 2-[(4-羟基-2-喹唑啉基)硫基]丙酸
• 英文名称: 2-(4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)propionic acid
• 英文别名: 2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)propanoic acid；2-(4-Oxo-1,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid；2-[(4-oxo-3H-quinazolin-2-yl)sulfanyl]propanoic acid
• CAS: 328977-86-2
• 化学式: C₁₁H₁₀N₂O₃S
• mdl: MFCD02946380
• 分子量: 250.278
• InChiKey: VYCHQMHTSPQPMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  N-甲基环己胺 、 2-[(4-羟基-2-喹唑啉基)硫基]丙酸 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 0.5h， 以29%的产率得到N-cyclohexyl-N-methyl-2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)propanamide
  参考文献：
  名称：

  2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

  摘要：

  Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

  DOI：

  10.1021/acsinfecdis.7b00275
• 作为产物：
  描述：

  邻氨基苯甲酸 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 2-[(4-羟基-2-喹唑啉基)硫基]丙酸
  参考文献：
  名称：

  2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

  摘要：

  Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

  DOI：

  10.1021/acsinfecdis.7b00275

文献信息

• Srinivasa Reddy; Naidu; Dubey, Indian Journal of Heterocyclic Chemistry, 2011, vol. 20, # 3, p. 257 - 260
  作者：Srinivasa Reddy、Naidu、Dubey

  DOI：——

  日期：——
• 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and <i>Mycobacterium tuberculosis</i>: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization
  作者：Dinakaran Murugesan、Peter C. Ray、Tracy Bayliss、Gareth A. Prosser、Justin R. Harrison、Kirsteen Green、Candice Soares de Melo、Tzu-Shean Feng、Leslie J. Street、Kelly Chibale、Digby F. Warner、Valerie Mizrahi、Ola Epemolu、Paul Scullion、Lucy Ellis、Jennifer Riley、Yoko Shishikura、Liam Ferguson、Maria Osuna-Cabello、Kevin D. Read、Simon R. Green、Dirk A. Lamprecht、Peter M. Finin、Adrie J. C. Steyn、Thomas R. Ioerger、Jim Sacchettini、Kyu Y. Rhee、Kriti Arora、Clifton E. Barry、Paul G. Wyatt、Helena I. M. Boshoff

  DOI：10.1021/acsinfecdis.7b00275

  日期：2018.6.8

  Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.