6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl]-2-hydroxy-4-oxo-2,5-hexdienoic acid | 868616-78-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl]-2-hydroxy-4-oxo-2,5-hexdienoic acid
• 英文别名: 6-[1-[(4-fluorophenyl)methyl]pyrrol-2-yl]-2-hydroxy-4-oxohexa-2,5-dienoic acid
• CAS: 868616-78-8
• 化学式: C₁₇H₁₄FNO₄
• 分子量: 315.301
• InChiKey: MITNEAVECVTJOK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.78
• 重原子数：
  23.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  79.53
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  1-(4-fluorobenzyl)-1H-pyrrole-2-carboxaldehyde 在 sodium ethanolate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 25.5h， 生成 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl]-2-hydroxy-4-oxo-2,5-hexdienoic acid
  参考文献：
  名称：

  Diketo Acids Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain

  摘要：

  HIV-1 整合酶（IN）和逆转录酶（RT）是病毒循环中的重要酶。RT 对 RNA 病毒基因组的逆转录至关重要，而 IN 则参与将 RT 产生的前病毒双链 DNA 插入宿主染色体。这种酶有两种相关功能：RNA 和 DNA 依赖性 DNA 聚合酶（RDDP 和 DDDP）以及核糖核酸酶 H（RNase H）。RNase H 的功能是催化选择性水解 RNA:DNA 异源双工复制中间体的 RNA 链。自从发现 HIV-1 RNase H 和 IN 的催化核心以非常相似的方式折叠，具有非常相似的活性位点几何结构，并显示出催化活性绝对需要的相同 DDE 三元组之后，一些研究人员致力于 IN 和 RNase H 双抑制剂的研究。我们对 IN 抑制剂的设计和合成有着长达十年的兴趣，这促使我们研究我们的化合物对 RNase H 的活性。报告和讨论了吡咯基和醌基二酮酸的活性结果。

  DOI：

  10.2174/092986711796504619

文献信息

• Diketo Acids Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain
  作者：R. Di Santo

  DOI：10.2174/092986711796504619

  日期：2011.8.1

  The HIV-1 integrase (IN) and reverse transcriptase (RT) are essential enzymes in the virus cycle. RT is crucial for the retrotranscription of the RNA viral genome, while IN is involved in the insertion in host chromosome of the proviral double strand DNA produced by RT. This enzyme has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the ribonuclease H (RNase H). The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. Since the discovery that catalytic cores of both HIV-1 RNase H and IN are folded in a very similar way, have very similar active site geometries, and show the same DDE triad absolutely required for catalytic activity, some researches were devoted to study IN and RNase H dual inhibitor. Our decennial interest in design and synthesis of IN inhibitors led us to study the activity of our compounds also on RNase H activity. The results of the activities showed by pyrrolyl and quinolonyl diketo acids are reported and discussed.

  HIV-1 整合酶（IN）和逆转录酶（RT）是病毒循环中的重要酶。RT 对 RNA 病毒基因组的逆转录至关重要，而 IN 则参与将 RT 产生的前病毒双链 DNA 插入宿主染色体。这种酶有两种相关功能：RNA 和 DNA 依赖性 DNA 聚合酶（RDDP 和 DDDP）以及核糖核酸酶 H（RNase H）。RNase H 的功能是催化选择性水解 RNA:DNA 异源双工复制中间体的 RNA 链。自从发现 HIV-1 RNase H 和 IN 的催化核心以非常相似的方式折叠，具有非常相似的活性位点几何结构，并显示出催化活性绝对需要的相同 DDE 三元组之后，一些研究人员致力于 IN 和 RNase H 双抑制剂的研究。我们对 IN 抑制剂的设计和合成有着长达十年的兴趣，这促使我们研究我们的化合物对 RNase H 的活性。报告和讨论了吡咯基和醌基二酮酸的活性结果。
• 6-(1-Benzyl-1<i>H</i>-pyrrol-2-yl)-2,4-dioxo-5-hexenoic Acids as Dual Inhibitors of Recombinant HIV-1 Integrase and Ribonuclease H, Synthesized by a Parallel Synthesis Approach
  作者：Roberta Costi、Mathieu Métifiot、Francesca Esposito、Giuliana Cuzzucoli Crucitti、Luca Pescatori、Antonella Messore、Luigi Scipione、Silvano Tortorella、Luca Zinzula、Ettore Novellino、Yves Pommier、Enzo Tramontano、Christophe Marchand、Roberto Di Santo

  DOI：10.1021/jm401040b

  日期：2013.11.14

  The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 mu M, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.