1-ethyl-3-(6-(2-methylpyrimidin-5-yl)-5-((tetrahydrofuran-3-yl)-methoxy)thiazolo[5,4-b]pyridin-2-yl)urea | 1470082-12-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-ethyl-3-(6-(2-methylpyrimidin-5-yl)-5-((tetrahydrofuran-3-yl)-methoxy)thiazolo[5,4-b]pyridin-2-yl)urea
• 英文别名: 1-Ethyl-3-[6-(2-methylpyrimidin-5-yl)-5-(tetrahydrofuran-3-ylmethoxy)thiazolo[5,4-b]pyridin-2-yl]urea；1-ethyl-3-[6-(2-methylpyrimidin-5-yl)-5-(oxolan-3-ylmethoxy)-[1,3]thiazolo[5,4-b]pyridin-2-yl]urea
• CAS: 1470082-12-2
• 化学式: C₁₉H₂₂N₆O₃S
• 分子量: 414.488
• InChiKey: FVWSCKNJICVDQN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  6-bromo-5-(tetrahydrofuran-3-ylmethoxy)[1,3]thiazolo[5,4-b]pyridin-2-amine 在 四(三苯基膦)钯 、 二正丁基氧化锡 、 碳酸氢钠 、 三乙胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 水 、 甲苯 为溶剂， 反应 0.75h， 生成 1-ethyl-3-(6-(2-methylpyrimidin-5-yl)-5-((tetrahydrofuran-3-yl)-methoxy)thiazolo[5,4-b]pyridin-2-yl)urea
  参考文献：
  名称：

  Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B

  摘要：

  A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.

  DOI：

  10.1021/jm401268f

文献信息

• Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B
  作者：Manoj G. Kale、Anandkumar Raichurkar、Shahul Hameed P、David Waterson、David McKinney、M. R. Manjunatha、Usha Kranthi、Krishna Koushik、Lalit kumar Jena、Vikas Shinde、Suresh Rudrapatna、Shubhada Barde、Vaishali Humnabadkar、Prashanti Madhavapeddi、Halesha Basavarajappa、Anirban Ghosh、VK Ramya、Supreeth Guptha、Sreevalli Sharma、Prakash Vachaspati、K.N. Mahesh Kumar、Jayashree Giridhar、Jitendar Reddy、Vijender Panduga、Samit Ganguly、Vijaykamal Ahuja、Sheshagiri Gaonkar、C. N. Naveen Kumar、Derek Ogg、Julie A. Tucker、P. Ann Boriack-Sjodin、Sunita M. de Sousa、Vasan K. Sambandamurthy、Sandeep R. Ghorpade

  DOI：10.1021/jm401268f

  日期：2013.11.14

  A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.