(2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3-(prop-2-ynyloxy)chroman | 1089147-17-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3-(prop-2-ynyloxy)chroman
• 英文别名: 3-O-propargyl-5,7,3',4'-O-tetrabenzyl epicatechin；3-O-propargyl-tetra-O-benzylepicatechin；3-O-propargyl-tetrabenzylepicatechin；(2R,3R)-2-[3,4-bis(phenylmethoxy)phenyl]-5,7-bis(phenylmethoxy)-3-prop-2-ynoxy-3,4-dihydro-2H-chromene
• CAS: 1089147-17-0
• 化学式: C₄₆H₄₀O₆
• 分子量: 688.82
• InChiKey: KDIIMSWGNXPAFA-AWSIMMLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.3
• 重原子数：
  52
• 可旋转键数：
  15
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  55.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3-(prop-2-ynyloxy)chroman 、 1-azidomethyl-3-nitrobenzene 在 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 乙腈 为溶剂， 以70%的产率得到2R,3R-4-[5,7-bis-benzyloxy-2-(3,4-bis-benzyloxyphenyl)chroman-3-yloxymethyl]-1-(3-nitrobenzyl)-1H-[1,2,3]triazole
  参考文献：
  名称：

  Inhibition of M. tuberculosis β-ketoacyl CoA reductase FabG4 (Rv0242c) by triazole linked polyphenol–aminobenzene hybrids: Comparison with the corresponding gallate counterparts

  摘要：

  Herein we report six novel triazole linked polyphenol-aminobenzene hybrids (3-8) as inhibitors of Mycobacterium tuberculosis FabG4 (Rv0242c), a less explored beta-ketoacyl CoA reductase that has immense potential to be the future anti-tuberculosis drug target due to its possible involvement in drug resistance and latent infection. Novel triazole linked polyphenol-aminobenzene hybrids have been synthesized, characterized and evaluated for their inhibitory activity against FabG4. All of them inhibit FabG4 at low micromolar concentrations. In silico docking study has been carried out to explain the experimental findings. A comparative study of these new inhibitors with previously reported gallate counterparts leads to structure-activity relations (SAR) of substituent linked to N-1 of triazole ring. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.01.014
• 作为产物：
  描述：

  (-)-epitaxifolin 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 36.5h， 生成 (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3-(prop-2-ynyloxy)chroman
  参考文献：
  名称：

  Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4

  摘要：

  我们首次报道了三唑-多酚混合化合物1和2的设计与合成，作为结核分枝杆菌FabG4（Rv0242c）酶的抑制剂。该领域的一项重大进展发生在几年前，FabG4的X射线晶体结构的公布帮助我们通过计算片段药物设计（FBDD）方法设计了这些抑制剂。化合物1表现出竞争抑制，其抑制常数（Ki）值为3.97 ± 0.02 μM。另一方面，化合物2被发现为混合型抑制剂，Ki值为0.88 ± 0.01 μM。使用等温滴定热量计（ITC）进行的热力学分析显示，这两种抑制剂都在NADH辅因子结合域结合。通过对M. smegmatis进行的罗丹明B实验确定的最小抑菌浓度（MIC）值表明它们具有良好的抗分枝杆菌特性。初步的结构-活性关系（SAR）研究支持了这些抑制剂的设计。这些化合物可能作为替代抗结核药物的先导化合物候选者。结核分枝杆菌家族的所有还原酶都有类似的酮酰还原酶（KAR）结构域。因此，这项工作可以外推以寻找其他还原酶的基于结构的抑制剂。

  DOI：

  10.1039/c3ob41676c

文献信息

• Design, synthesis and RNase A inhibition activity of catechin and epicatechin and nucleobase chimeric molecules
  作者：Basab Roy、Sansa Dutta、Anupma Chowdhary、Amit Basak、Swagata Dasgupta

  DOI：10.1016/j.bmcl.2008.09.051

  日期：2008.10

  Several novel catechin/epicatechin and nucleobase chimeric molecules 1-6 have been synthesized via azide-alkyne click chemistry. The structures of these hybrids have been confirmed by NMR and mass spectroscopic data. The synthesized molecules were tested for their RNase A inhibition activities. Gel-based assays showed inhibition in micromolar concentrations. The extent of inhibition was found to be dependent upon the nature of base as well as the configuration at C-3 position of catechin. (C) 2008 Elsevier Ltd. All rights reserved.
• Design, synthesis and bioactivity of catechin/epicatechin and 2-azetidinone derived chimeric molecules
  作者：Basab Roy、Arindam Chakraborty、Sudip K. Ghosh、Amit Basak

  DOI：10.1016/j.bmcl.2009.04.084

  日期：2009.12

  A new class of chimeric molecules have been developed. These are based on polyphenols like catechin and epicatechin and monocyclic beta-lactams. The two units are joined via a triazole linker using the 'Click Chemistry' conditions. The compounds showed good to weak antibacterial activity against Escherichia coli as well as moderate inhibition of RNase A. (C) 2009 Elsevier Ltd. All rights reserved.
• Inhibition of M. tuberculosis β-ketoacyl CoA reductase FabG4 (Rv0242c) by triazole linked polyphenol–aminobenzene hybrids: Comparison with the corresponding gallate counterparts
  作者：Deb Ranjan Banerjee、Kalyan Senapati、Rupam Biswas、Amit K. Das、Amit Basak

  DOI：10.1016/j.bmcl.2015.01.014

  日期：2015.3

  Herein we report six novel triazole linked polyphenol-aminobenzene hybrids (3-8) as inhibitors of Mycobacterium tuberculosis FabG4 (Rv0242c), a less explored beta-ketoacyl CoA reductase that has immense potential to be the future anti-tuberculosis drug target due to its possible involvement in drug resistance and latent infection. Novel triazole linked polyphenol-aminobenzene hybrids have been synthesized, characterized and evaluated for their inhibitory activity against FabG4. All of them inhibit FabG4 at low micromolar concentrations. In silico docking study has been carried out to explain the experimental findings. A comparative study of these new inhibitors with previously reported gallate counterparts leads to structure-activity relations (SAR) of substituent linked to N-1 of triazole ring. (C) 2015 Elsevier Ltd. All rights reserved.
• Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4
  作者：Deb Ranjan Banerjee、Debajyoti Dutta、Baisakhee Saha、Sudipta Bhattacharyya、Kalyan Senapati、Amit K. Das、Amit Basak

  DOI：10.1039/c3ob41676c

  日期：——

  We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 μM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 μM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure–activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes.

  我们首次报道了三唑-多酚混合化合物1和2的设计与合成，作为结核分枝杆菌FabG4（Rv0242c）酶的抑制剂。该领域的一项重大进展发生在几年前，FabG4的X射线晶体结构的公布帮助我们通过计算片段药物设计（FBDD）方法设计了这些抑制剂。化合物1表现出竞争抑制，其抑制常数（Ki）值为3.97 ± 0.02 μM。另一方面，化合物2被发现为混合型抑制剂，Ki值为0.88 ± 0.01 μM。使用等温滴定热量计（ITC）进行的热力学分析显示，这两种抑制剂都在NADH辅因子结合域结合。通过对M. smegmatis进行的罗丹明B实验确定的最小抑菌浓度（MIC）值表明它们具有良好的抗分枝杆菌特性。初步的结构-活性关系（SAR）研究支持了这些抑制剂的设计。这些化合物可能作为替代抗结核药物的先导化合物候选者。结核分枝杆菌家族的所有还原酶都有类似的酮酰还原酶（KAR）结构域。因此，这项工作可以外推以寻找其他还原酶的基于结构的抑制剂。