(3R,6S)-6-(((6-methoxy-1,5-naphthyridin-4-yl)oxy)methyl)tetrahydro-2H-pyran-3-amine | 881656-92-4

• 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: (3R,6S)-6-(((6-methoxy-1,5-naphthyridin-4-yl)oxy)methyl)tetrahydro-2H-pyran-3-amine
• 英文别名: (3R,6S)-6-[(6-methoxy-1,5-naphthyridin-4-yl)oxymethyl]oxan-3-amine
• CAS: 881656-92-4
• 化学式: C₁₅H₁₉N₃O₃
• 分子量: 289.334
• InChiKey: CKOIZOTZHQXBMB-MNOVXSKESA-N

物化性质

• 沸点：
  429.8±45.0 °C(Predicted)
• 密度：
  1.210±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 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：
  79.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噻嗪-6-甲醛 、 (3R,6S)-6-(((6-methoxy-1,5-naphthyridin-4-yl)oxy)methyl)tetrahydro-2H-pyran-3-amine 在 sodium tetrahydroborate 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 2.0h， 以55%的产率得到6-((((3R,6S)-6-(((6-methoxy-1,5-naphthyridin-4-yl)oxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)methyl)-2H-pyrido[3,2-b][1,4]-thiazin-3(4H)-one
  参考文献：
  名称：

  Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity

  摘要：

  There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K channel block. On the other hand, analog 49e displayed lower hERG K channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.

  DOI：

  10.1021/jm400963y
• 作为产物：
  描述：

  6-甲氧基-1,5-萘啶-4(1h)-酮 在 偶氮二甲酸二异丙酯 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 5.0h， 生成 (3R,6S)-6-(((6-methoxy-1,5-naphthyridin-4-yl)oxy)methyl)tetrahydro-2H-pyran-3-amine
  参考文献：
  名称：

  通过结构和物理化学优化降低氨基哌啶-萘啶连接的 NBTI 抗菌剂的 hERG 抑制活性

  摘要：

  新型细菌拓扑异构酶抑制剂 (NBTI) 是一类重要的新型抗菌药物，靶向细菌 II 型拓扑异构酶（DNA 促旋酶和拓扑异构酶 IV）。尽管它们具有强大的抗菌活性，但它们遭受有害的类别相关的 hERG 阻塞。在这项研究中，我们设计并合成了一个优化的 NBTI 文库，其中包含不同的接头部分，这些接头部分表现出降低的 hERG 抑制作用，并分别保留了对金黄色葡萄球菌和大肠杆菌的 DNA 促旋酶和拓扑异构酶 IV 的抑制效力，以及有效的抗菌活性。用极性基团取代接头的叔胺导致降低的hERG抑制。化合物17相对于我们之前发表的 NBTI 类似物，表达了对革兰氏阳性和革兰氏阴性细菌的纳摩尔酶抑制效力和抗菌活性以及降低的 hERG 抑制。在这里，我们指出了影响其 hERG 抑制活性的一些重要的 NBTI 结构特征。

  DOI：

  10.1016/j.bioorg.2022.106087

文献信息

• Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond Halogen-Bonding Interactions
  作者：Maja Kokot、Doroteja Novak、Irena Zdovc、Marko Anderluh、Martina Hrast、Nikola Minovski

  DOI：10.3390/antibiotics12050930

  日期：——

  Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.g., hydrogen-bonding and/or hydrophobic interactions), we introduced various non-halogen groups at the p-position of the phenyl RHS moiety. Considering the hydrophobic nature of amino acid residues delineating the NBTI’s binding pocket in bacterial topoisomerases, we demonstrated that designed NBTIs cannot establish any hydrogen-bonding interactions with the enzyme; hydrophobic interactions are feasible in all respects, while halogen-bonding interactions are apparently the most preferred.

  新型细菌拓扑异构酶抑制剂（NBTI）是一类新的抗菌剂，以细菌 II 型拓扑异构酶（DNA 回旋酶和拓扑异构酶 IV）为靶标。我们最近公布的 NBTI 配体与 DNA gyrase 和 DNA 复合物的晶体结构显示，位于苯基右侧 (RHS) 分子对位的卤原子能够与酶建立牢固的对称二叉卤素键；这是这些 NBTI 具有出色的酶抑制效力和抗菌活性的原因。为了进一步评估其他相互作用（如氢键和/或疏水相互作用）的可能性，我们在苯基 RHS 分子的 p 位引入了各种非卤素基团。考虑到细菌拓扑异构酶中划定 NBTI 结合袋的氨基酸残基的疏水性，我们证明设计的 NBTI 不能与酶建立任何氢键相互作用；疏水相互作用在所有方面都是可行的，而卤键相互作用显然是最可取的。
• Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity
  作者：Jean-Philippe Surivet、Cornelia Zumbrunn、Georg Rueedi、Christian Hubschwerlen、Daniel Bur、Thierry Bruyère、Hans Locher、Daniel Ritz、Wolfgang Keck、Peter Seiler、Christopher Kohl、Jean-Christophe Gauvin、Azely Mirre、Verena Kaegi、Marina Dos Santos、Mika Gaertner、Jonathan Delers、Michel Enderlin-Paput、Maria Boehme

  DOI：10.1021/jm400963y

  日期：2013.9.26

  There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K channel block. On the other hand, analog 49e displayed lower hERG K channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.
• Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations
  作者：Maja Kokot、Matjaž Weiss、Irena Zdovc、Marko Anderluh、Martina Hrast、Nikola Minovski

  DOI：10.1016/j.bioorg.2022.106087

  日期：2022.11

  and topoisomerase IV of Staphylococcus aureus and Escherichia coli, respectively, as well as potent antibacterial activities. Substitution of the linker’s tertiary amine with polar groups outcome in diminished hERG inhibition. Compound 17 expresses nanomolar enzyme inhibitory potency and antibacterial activity against both Gram-positive and Gram-negative bacteria as well as reduced hERG inhibition relative

  新型细菌拓扑异构酶抑制剂 (NBTI) 是一类重要的新型抗菌药物，靶向细菌 II 型拓扑异构酶（DNA 促旋酶和拓扑异构酶 IV）。尽管它们具有强大的抗菌活性，但它们遭受有害的类别相关的 hERG 阻塞。在这项研究中，我们设计并合成了一个优化的 NBTI 文库，其中包含不同的接头部分，这些接头部分表现出降低的 hERG 抑制作用，并分别保留了对金黄色葡萄球菌和大肠杆菌的 DNA 促旋酶和拓扑异构酶 IV 的抑制效力，以及有效的抗菌活性。用极性基团取代接头的叔胺导致降低的hERG抑制。化合物17相对于我们之前发表的 NBTI 类似物，表达了对革兰氏阳性和革兰氏阴性细菌的纳摩尔酶抑制效力和抗菌活性以及降低的 hERG 抑制。在这里，我们指出了影响其 hERG 抑制活性的一些重要的 NBTI 结构特征。