9-cyclopropyl-7-{(R)-3-[(S)-1-(dimethylamino)ethyl]pyrrolidin-1-yl}-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione | 1297655-74-3

• 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-7-{(R)-3-[(S)-1-(dimethylamino)ethyl]pyrrolidin-1-yl}-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione
• 英文别名: 9-cyclopropyl-7-[(3R)-3-[(1S)-1-(dimethylamino)ethyl]pyrrolidin-1-yl]-6-fluoro-8-methoxy-[1,2]thiazolo[5,4-b]quinoline-3,4-dione
• CAS: 1297655-74-3
• 化学式: C₂₂H₂₇FN₄O₃S
• 分子量: 446.546
• InChiKey: LXGUTKQICOKDDJ-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  90.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  9-cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione 、 -N,N,α-trimethyl-3-pyrrolidinemethanamine 在 N,N-二异丙基乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 15.0h， 生成 9-cyclopropyl-7-{(R)-3-[(S)-1-(dimethylamino)ethyl]pyrrolidin-1-yl}-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione
  参考文献：
  名称：

  Exploration of the Activity of 7-Pyrrolidino-8-methoxyisothiazoloquinolones against Methicillin-Resistant Staphylococcus aureus (MRSA)

  摘要：

  A series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC <= 0.25 mu g/mL against quinolone-resistant MRSA strains. The stereochemical preference was explored for a series of 1 ''-methyl-3'-aminomethylpyrrolidine analogues. Antibacterial activity was generally more favorable with 3'-R, 1 ''-S configuration. Substitution on the 3'-aminomethyl nitrogen tended to decrease activity, while potency was maintained with disubstitution or aryl substitution at the 1 ''-carbon. The 7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl] analogue (6a(R,S)) and the (R)-7-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl] analogue (7a(R)) were found to be the ITQs with the most promising antibacterial profiles. The MICs of these select ITQs versus a panel of clinical MRSA strains were determined, and the ITQs were found to have 8- to 16-fold greater potency than linezolid. These analogues were also evaluated for inhibition of the target enzymes, topoisomerase IV and DNA gyrase, from both wild-type and multidrug resistant strains. The ITQs were up to >30 times more inhibitory against these targets than the fluoroquinolone moxifloxacin.

  DOI：

  10.1021/jm101604v

文献信息

• Exploration of the Activity of 7-Pyrrolidino-8-methoxyisothiazoloquinolones against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)
  作者：Ha Young Kim、Jason A. Wiles、Qiuping Wang、Godwin C. G. Pais、Edlaine Lucien、Akihiro Hashimoto、David M. Nelson、Jane A. Thanassi、Steven D. Podos、Milind Deshpande、Michael J. Pucci、Barton J. Bradbury

  DOI：10.1021/jm101604v

  日期：2011.5.12

  A series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC <= 0.25 mu g/mL against quinolone-resistant MRSA strains. The stereochemical preference was explored for a series of 1 ''-methyl-3'-aminomethylpyrrolidine analogues. Antibacterial activity was generally more favorable with 3'-R, 1 ''-S configuration. Substitution on the 3'-aminomethyl nitrogen tended to decrease activity, while potency was maintained with disubstitution or aryl substitution at the 1 ''-carbon. The 7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl] analogue (6a(R,S)) and the (R)-7-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl] analogue (7a(R)) were found to be the ITQs with the most promising antibacterial profiles. The MICs of these select ITQs versus a panel of clinical MRSA strains were determined, and the ITQs were found to have 8- to 16-fold greater potency than linezolid. These analogues were also evaluated for inhibition of the target enzymes, topoisomerase IV and DNA gyrase, from both wild-type and multidrug resistant strains. The ITQs were up to >30 times more inhibitory against these targets than the fluoroquinolone moxifloxacin.