(R)-<3-<3-fluoro-4-(4-thiomorpholinyl)phenyl>-2-oxo-5-oxazolidinyl>methyl methanesulfonate | 174678-78-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻嗪类
• 英文名称: (R)-<3-<3-fluoro-4-(4-thiomorpholinyl)phenyl>-2-oxo-5-oxazolidinyl>methyl methanesulfonate
• 英文别名: (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl methane sulfonate；[(5R)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate
• CAS: 174678-78-5
• 化学式: C₁₅H₁₉FN₂O₅S₂
• 分子量: 390.457
• InChiKey: FZDJWMMHVWWLSQ-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  110
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (R)-<3-<3-fluoro-4-(4-thiomorpholinyl)phenyl>-2-oxo-5-oxazolidinyl>methyl methanesulfonate 在 吡啶 、 sodium azide 、 水 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 sutezolid
  参考文献：
  名称：

  Identification of a Novel Oxazolidinone (U-100480) with Potent Antimycobacterial Activity

  摘要：

  During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's less than or equal to 0.125 mu g/mL). Oxazolidinones 6 and 8 exhibit MIC(90) values of 0.50 mu g/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 mu g/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmacokinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

  DOI：

  10.1021/jm950956y
• 作为产物：
  描述：

  3,4-二氟硝基苯 在 正丁基锂 、 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 26.92h， 生成 (R)-<3-<3-fluoro-4-(4-thiomorpholinyl)phenyl>-2-oxo-5-oxazolidinyl>methyl methanesulfonate
  参考文献：
  名称：

  新型基于利奈唑胺的恶唑烷酮类药物作为有效的抗念珠菌病和抗结核药

  摘要：

  由于病态的共同发病机制和免疫功能低下患者的增加，对新的抗真菌和抗结核药物的探索是当务之急。前进的方法之一是探索和重新利用已建立的药效团以用于所需的应用。恶唑烷酮是众所周知的抗菌剂，很少有研究报道利用它们的抗真菌特性。在此，我们报告了一系列基于利奈唑胺的恶唑烷酮类药物作为有效的抗念珠菌病和抗结核药物的设计和合成。研究表明，两种新型恶唑烷酮2和3a对不同的念珠菌表现出优异的抗念珠菌病活性真菌菌株，优于标准药物。机理和对接研究表明，恶唑烷酮类是麦角甾醇生物合成途径的更好抑制剂，比所使用的对照组更好。此外，恶唑烷酮2和3a对M. tuberculosis H 37 Rv也表现出显着的抑制活性，MIC 值分别为 1 和 2 μg/ml。计算研究证明了化合物与转录调节阻遏蛋白的结合，分子动力学模拟加强了这一点。药效团建模实验验证了两种靶蛋白的分子对接结果。

  DOI：

  10.1016/j.bioorg.2022.105869

文献信息

• RETRACTED ARTICLE: Design, synthesis of novel oxazolidino-amides/sulfonamides conjugates and their impact on antibacterial activity
  作者：Yarlagadda Bharath、Gopi Reddy Alugubelli、Reddymasu Sreenivasulu、Mandava. V. Basaveswara Rao

  DOI：10.1007/s11696-017-0298-1

  日期：2018.2

  AbstractIn view of generating new compounds for future drug development, we have synthesized oxazolidinones library of aryl amides and aryl sulfonamide derivatives. These compounds were screened in vitro against panel of susceptible and resistant Gram-positive (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa), fungi (Candida albicans) strains, and Mycobacterium

  摘要考虑到产生用于未来药物开发的新化合物，我们已经合成了芳基酰胺和芳基磺酰胺衍生物的恶唑烷酮文库。这些化合物在体外针对敏感和耐药的革兰氏阳性菌（金黄色葡萄球菌和枯草芽孢杆菌），革兰氏阴性菌（铜绿假单胞菌），真菌（白色念珠菌）和结核分枝杆菌（Mtb）进行了筛选。其中，对10d和11a化合物已针对12种真菌菌株进行了评估，并显示出显着的抗真菌活性，其效力比氟康唑高约37倍。 图形概要
• Structure-Activity Relationship (SAR) Studies on Oxazolidinone Antibacterial Agents. 1. Conversion of 5-Substituent on Oxazolidinone.
  作者：Ryukou TOKUYAMA、Yoshiei TAKAHASHI、Yayoi TOMITA、Tomio SUZUKI、Toshihiko YOSHIDA、Nobuhiko IWASAKI、Noriyuki KADO、Eiichi OKEZAKI、Osamu NAGATA

  DOI：10.1248/cpb.49.347

  日期：——

  A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (=O) by thiocarbonyl sulfur (=S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.

  描述了一项关于作为抗菌剂的5-取代恶唑烷酮的构效关系（SAR）研究。通过将5-乙酰氨基甲基部分转化为其他功能基团，制备并评价了这些恶唑烷酮的抗菌活性。延长甲撑链（8）和将乙酰氨基部分转化为胍基部分（12）降低了抗菌活性。用硫代羰基硫（=S）取代羰基氧（=O）增强了体外抗菌活性。特别是化合物16，具有5-硫脲基团，其体外活性比利奈唑胺强4-8倍。我们的SAR研究表明，5-取代基的转化对抗菌活性有很大影响。
• Identification of a Novel Oxazolidinone (U-100480) with Potent Antimycobacterial Activity
  作者：Michael R. Barbachyn、Douglas K. Hutchinson、Steven J. Brickner、Michael H. Cynamon、James O. Kilburn、Sally P. Klemens、Suzanne E. Glickman、Kevin C. Grega、Susan K. Hendges、Dana S. Toops、Charles W. Ford、Gary E. Zurenko

  DOI：10.1021/jm950956y

  日期：1996.1.1

  During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's less than or equal to 0.125 mu g/mL). Oxazolidinones 6 and 8 exhibit MIC(90) values of 0.50 mu g/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 mu g/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmacokinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.
• Novel linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents
  作者：Shaik Faazil、M. Shaheer Malik、Saleh A. Ahmed、Reem I. Alsantali、Poornachandra Yedla、Meshari A. Alsharif、Iqbal N. Shaikh、Ahmed Kamal

  DOI：10.1016/j.bioorg.2022.105869

  日期：2022.9

  Oxazolidinones are well-known antibacterial agents, with few investigations reported to exploit their antifungal properties. Herein, we report the design and synthesis of a series of linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents. Studies revealed that two of the novel oxazolidinones 2 and 3a exhibited excellent anticandidiasis activity against different Candida fungus

  由于病态的共同发病机制和免疫功能低下患者的增加，对新的抗真菌和抗结核药物的探索是当务之急。前进的方法之一是探索和重新利用已建立的药效团以用于所需的应用。恶唑烷酮是众所周知的抗菌剂，很少有研究报道利用它们的抗真菌特性。在此，我们报告了一系列基于利奈唑胺的恶唑烷酮类药物作为有效的抗念珠菌病和抗结核药物的设计和合成。研究表明，两种新型恶唑烷酮2和3a对不同的念珠菌表现出优异的抗念珠菌病活性真菌菌株，优于标准药物。机理和对接研究表明，恶唑烷酮类是麦角甾醇生物合成途径的更好抑制剂，比所使用的对照组更好。此外，恶唑烷酮2和3a对M. tuberculosis H 37 Rv也表现出显着的抑制活性，MIC 值分别为 1 和 2 μg/ml。计算研究证明了化合物与转录调节阻遏蛋白的结合，分子动力学模拟加强了这一点。药效团建模实验验证了两种靶蛋白的分子对接结果。