| 1372616-36-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• CAS: 1372616-36-8
• 化学式: C₅₆H₇₀N₆O₁₃
• 分子量: 1035.2
• InChiKey: BWDTVIVNIJMQGS-WQPMZEBSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.62
• 重原子数：
  75.0
• 可旋转键数：
  11.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  237.48
• 氢给体数：
  4.0
• 氢受体数：
  18.0

反应信息

• 作为反应物：
  描述：

  N-异丁基哌嗪 、 在 manganese(IV) oxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以48 %的产率得到(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-32-(4-{4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}butoxy)-11-methoxy-3,7,12,14,16,18,22-heptamethyl-30-[4-(2-methylpropyl)piperazin-1-yl]-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo [23.11.1.1^4,7.0^5,36.0^26,35.0²⁸'³³]octatriaconta-1(36),2,4,9,19,21,25,28(33),29,31,34-undecaen-13-yl acetate
  参考文献：
  名称：

  [EN] RIFAMYCIN ANALOGS
  [FR] ANALOGUES DE RIFAMYCINE

  摘要：

  Provided herein are compounds that are potent inhibitors of theMycobacterium tuberculosis(MTB) RNA polymerase (RNAP), which exhibit significantly reduced activation of the human pregnane X receptor (hPXR), resulting in dramatically reduced induction of hepatic cytochromes P450 2C9 and 3A4 (CYP2C9, CYP3A4), as well as a number of Phase II metabolism enzymes. Also provided herein are pharmaceutical compositions comprising the compounds, and methods of treating tuberculosis using the compounds.

  公开号：

  WO2022159491A1
• 作为产物：
  描述：

  1-(benzyloxy)-3-(4-bromobutoxy)-2-nitrobenzene 在 盐酸 、 20 % Pd(OH)2/C 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 乙腈 为溶剂， 20.0 ℃ 、275.8 kPa 条件下， 反应 40.5h， 生成
  参考文献：
  名称：

  Structure-Based Design of Novel Benzoxazinorifamycins with Potent Binding Affinity to Wild-Type and Rifampin-Resistant MutantMycobacterium tuberculosisRNA Polymerases

  摘要：

  By utilization of three-dimensional structure information of rifamycins bound to RNA polymerase (RNAP) and the human pregnane X receptor (hPXR), representative examples (2b-d) of a novel subclass of benzoxazinorifamycins have been synthesized. Relative to rifalazil (2a), these analogues generally display superior affinity toward wild-type and Rif-resistant mutants of the Mycobacterium tuberculosis RNAP but lowered antitubercular activity in cell culture under both aerobic and anaerobic conditions. Lowered affinity toward hPXR for some of the analogues is also observed, suggesting a potential for reduced Cyp450 induction activity. Mouse and human microsomal studies of analogue 2b show it to have excellent metabolic stability. Mouse pharmacokinetics in plasma and lung show accumulation of 2b but with a half-life suggesting nonoptimal pharmacokinetics. These studies demonstrate proof of principle for this subclass of rifamycins and support further expansion of structure-activity relationships (SARs) toward uncovering analogues with development potential.

  DOI：

  10.1021/jm201716n

文献信息

• [EN] ANTIMICROBIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIMICROBIENS
  申请人：UNIV MICHIGAN

  公开号：WO2013086415A1

  公开（公告）日：2013-06-13

  Provided herein is technology relating to antimicrobial compounds and particularly, but not exclusively, to analogs of rifalazil having increased inhibition of RNA polymerase and decreased induction of human cy-tochrome P450. The compounds have an increased affinity for a bacterial RNA polymerase (e.g., a MTB RNA polymerase) and a decreased affinity for a human pregnane X receptor. Thus, in some embodiments, the steric clash of A or R with residues in the binding pocket of the human pregnane X receptor reduces an affinity of the compound for the human pregnane X receptor. Consequently, in some embodiments the steric clash thus reduces the induction (e.g., an activity) of a cytochrome P450 and/or other related proteins.

  本文提供了与抗菌化合物相关的技术，特别是但不仅限于具有增强RNA聚合酶抑制作用和减少诱导人类细胞色素P450的利法拉唑类似物。这些化合物对细菌RNA聚合酶（例如结核分枝杆菌RNA聚合酶）具有增强亲和力，并对人类孕烷X受体具有降低的亲和力。因此，在某些实施例中，化合物与人类孕烷X受体结合口袋中残基的空间阻碍A或R，降低了化合物对人类孕烷X受体的亲和力。因此，在某些实施例中，这种空间阻碍减少了细胞色素P450和/或其他相关蛋白的诱导（例如活性）。
• Optimization of Benzoxazinorifamycins to Improve <i>Mycobacterium tuberculosis</i> RNA Polymerase Inhibition and Treatment of Tuberculosis
  作者：Walajapet Rajeswaran、Shireen R. Ashkar、Pil H. Lee、Larisa Yeomans、Yeonoh Shin、Scott G. Franzblau、Katsuhiko S. Murakami、Hollis D. Showalter、George A. Garcia

  DOI：10.1021/acsinfecdis.1c00636

  日期：2022.8.12
• Structure-Based Design of Novel Benzoxazinorifamycins with Potent Binding Affinity to Wild-Type and Rifampin-Resistant Mutant<i>Mycobacterium tuberculosis</i>RNA Polymerases
  作者：Sumandeep K. Gill、Hao Xu、Paul D. Kirchhoff、Tomasz Cierpicki、Anjanette J. Turbiak、Baojie Wan、Nan Zhang、Kuan-Wei Peng、Scott G. Franzblau、George A. Garcia、H. D. Hollis Showalter

  DOI：10.1021/jm201716n

  日期：2012.4.26

  By utilization of three-dimensional structure information of rifamycins bound to RNA polymerase (RNAP) and the human pregnane X receptor (hPXR), representative examples (2b-d) of a novel subclass of benzoxazinorifamycins have been synthesized. Relative to rifalazil (2a), these analogues generally display superior affinity toward wild-type and Rif-resistant mutants of the Mycobacterium tuberculosis RNAP but lowered antitubercular activity in cell culture under both aerobic and anaerobic conditions. Lowered affinity toward hPXR for some of the analogues is also observed, suggesting a potential for reduced Cyp450 induction activity. Mouse and human microsomal studies of analogue 2b show it to have excellent metabolic stability. Mouse pharmacokinetics in plasma and lung show accumulation of 2b but with a half-life suggesting nonoptimal pharmacokinetics. These studies demonstrate proof of principle for this subclass of rifamycins and support further expansion of structure-activity relationships (SARs) toward uncovering analogues with development potential.
• [EN] RIFAMYCIN ANALOGS<br/>[FR] ANALOGUES DE RIFAMYCINE
  申请人：[en]THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：WO2022159491A1

  公开（公告）日：2022-07-28

  Provided herein are compounds that are potent inhibitors of theMycobacterium tuberculosis(MTB) RNA polymerase (RNAP), which exhibit significantly reduced activation of the human pregnane X receptor (hPXR), resulting in dramatically reduced induction of hepatic cytochromes P450 2C9 and 3A4 (CYP2C9, CYP3A4), as well as a number of Phase II metabolism enzymes. Also provided herein are pharmaceutical compositions comprising the compounds, and methods of treating tuberculosis using the compounds.