N-cyclohexyl-N-methyl-2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-cyclohexyl-N-methyl-2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide
• 英文别名: N-cyclohexyl-N-methyl-2-[(4-oxo-3H-quinazolin-2-yl)sulfanyl]acetamide
• 化学式: C₁₇H₂₁N₃O₂S
• 分子量: 331.439
• InChiKey: DJYIEFYUPAKSNK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  87.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-巯基-4(3H)-喹唑酮 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 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 12.5h， 生成 N-cyclohexyl-N-methyl-2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide
  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

• 1H-Benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones: Design, synthesis and antitubercular activity
  作者：Fernanda Souza Macchi、Kenia Pissinate、Anne Drumond Villela、Bruno Lopes Abbadi、Valnês Rodrigues-Junior、Débora Dreher Nabinger、Stefani Altenhofen、Nathalia Sperotto、Adílio da Silva Dadda、Fernanda Teixeira Subtil、Talita Freitas de Freitas、Ana Paula Erhart Rauber、Ana Flávia Borsoi、Carla Denise Bonan、Cristiano Valim Bizarro、Luiz Augusto Basso、Diógenes Santiago Santos、Pablo Machado

  DOI：10.1016/j.ejmech.2018.06.005

  日期：2018.7

  zebrafish (Danio rerio) toxicity models. 3,4-Dihydroquinazolin-4-ones 9q and 9w were considered the lead compounds of these series of molecules with MIC values of 0.24 μM and 0.94 μM against M. tuberculosis H37Rv, respectively. Taken together, these data indicate that this class of compounds may furnish candidates for future development of novel anti-TB drugs.

  使用经典的杂交方法，合成了一系列1 H-苯并[ d ]咪唑和3,4-二氢喹唑啉-4-酮（39个实例），并被评估为结核分枝杆菌生长的抑制剂。化学修饰研究产生了有效的抗结核药，对结核分枝杆菌H37Rv菌株的最低抑菌浓度（MIC）值低至0.24μM。此外，合成的化合物对一线药物具有四个不同耐药水平的四个耐药菌株具有活性。这些分子对带有IC 50s的HepG2，HaCat和Vero细胞无明显毒性 > 30μM。使用MTT和中性红分析评估了哺乳动物细胞培养物中的生存力。此外，一些3,4-二氢喹唑啉-4-酮表现出心脏毒性，在斑马鱼中没有神经毒性或形态学改变的信号（低风险斑马鱼）毒性的模型。3,4-二氢喹唑啉-4-酮9q和9w被认为是该系列分子中针对结核分枝杆菌H37Rv的MIC值为0.24μM和0.94μM的先导化合物。综合来看，这些数据表明这类化合物可为新型抗结核药物的未来开发提供候选。
• 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.