9-cyclopropyl-6-fluoro-7-isoquinolin-6-yl-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione

• 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: 9-cyclopropyl-6-fluoro-7-isoquinolin-6-yl-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione
• 英文别名: 9-Cyclopropyl-6-fluoro-7-isoquinolin-6-yl-8-methoxy-[1,2]thiazolo[5,4-b]quinoline-3,4-dione
• 化学式: C₂₃H₁₆FN₃O₃S
• 分子量: 433.463
• InChiKey: YQBZZXCNAOOMLT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  96.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-溴异喹啉 在 四(三苯基膦)钯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 potassium acetate 、 碳酸氢钠 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 9-cyclopropyl-6-fluoro-7-isoquinolin-6-yl-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione
  参考文献：
  名称：

  Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains:  Effects of Structural Modifications at the 6-, 7-, and 8-Positions

  摘要：

  We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 mu g/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.

  DOI：

  10.1021/jm060844e

文献信息

• Isothiazoloquinolones and related compounds as anti-infective agents
  申请人：Bradbury James Barton

  公开号：US20050075363A1

  公开（公告）日：2005-04-07

  The invention provides compounds and salts of Formula I and Formula II: which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables A 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A 8 and R 9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

  本发明提供了式I和式II的化合物和盐：它们具有抗微生物活性。本发明还提供了有用于制备式I和式II化合物的新型合成中间体。其中变量A1、R2、R3、R5、R6、R7、A8和R9在此有定义。本文所披露的式I和式II的某些化合物是细菌DNA合成和细菌复制的有效和选择性抑制剂。本发明还提供了抗微生物组合物，包括含有一个或多个式I或式II化合物和一个或多个载体、赋形剂或稀释剂的制药组合物。这样的组合物可能仅包含式I或式II的化合物作为唯一活性剂，也可能包含式I或式II的化合物和一个或多个其他活性剂的组合。本发明还提供了治疗动物微生物感染的方法。
• ISOTHIAZOLOQUINOLONES AND RELATED COMPOUNDS AS ANTI-INFECTIVE AGENTS
  申请人：Bradbury Barton James

  公开号：US20110223132A1

  公开（公告）日：2011-09-15

  The invention provides compounds and salts of Formula I and Formula which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables A 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A 8 and R 9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

  本发明提供了具有抗微生物活性的公式I和公式II的化合物和盐。本发明还提供了在制备公式I和公式II化合物中有用的新型合成中间体。变量A1、R2、R3、R5、R6、R7、A8和R9在此定义。本文所披露的某些公式I和公式II的化合物是细菌DNA合成和细菌复制的强效和选择性抑制剂。本发明还提供抗微生物组合物，包括含有一个或多个公式I或公式II化合物和一个或多个载体、赋形剂或稀释剂的药物组合物。这些组合物可以仅包含一个公式I或公式II化合物作为唯一活性剂，也可以包含一个公式I或公式II化合物和一个或多个其他活性剂的组合物。本发明还提供了治疗动物微生物感染的方法。
• Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains:  Effects of Structural Modifications at the 6-, 7-, and 8-Positions
  作者：Qiuping Wang、Edlaine Lucien、Akihiro Hashimoto、Godwin C. G. Pais、David M. Nelson、Yongsheng Song、Jane A. Thanassi、Christopher W. Marlor、Christy L. Thoma、Jijun Cheng、Steven D. Podos、Yangsi Ou、Milind Deshpande、Michael J. Pucci、Douglas D. Buechter、Barton J. Bradbury、Jason A. Wiles

  DOI：10.1021/jm060844e

  日期：2007.1.1

  We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 mu g/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.