3-(1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-3-yl)-1H-pyrazole-5-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 3-(1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-3-yl)-1H-pyrazole-5-carboxylic acid
• 英文别名: 3-[1-[(4-fluorophenyl)methyl]-4-phenyl-pyrrol-3-yl]-1H-pyrazole-5-carboxylic acid；3-[1-[(4-fluorophenyl)methyl]-4-phenylpyrrol-3-yl]-1H-pyrazole-5-carboxylic acid
• 化学式: C₂₁H₁₆FN₃O₂
• 分子量: 361.375
• InChiKey: UYBDGMZOPHQOFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  70.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  ethyl 3-(1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-3-yl)-1H-pyrazole-5-carboxylate 在 水 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以65%的产率得到3-(1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-3-yl)-1H-pyrazole-5-carboxylic acid
  参考文献：
  名称：

  Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV-1 Ribonuclease H Function of Reverse Transcriptase

  摘要：

  Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenyl-pyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.

  DOI：

  10.1021/acsmedchemlett.9b00617

文献信息

• Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV-1 Ribonuclease H Function of Reverse Transcriptase
  作者：Antonella Messore、Angela Corona、Valentina Noemi Madia、Francesco Saccoliti、Valeria Tudino、Alessandro De Leo、Luigi Scipione、Daniela De Vita、Giorgio Amendola、Salvatore Di Maro、Ettore Novellino、Sandro Cosconati、Mathieu Métifiot、Marie-Line Andreola、Piera Valenti、Francesca Esposito、Nicole Grandi、Enzo Tramontano、Roberta Costi、Roberto Di Santo

  DOI：10.1021/acsmedchemlett.9b00617

  日期：2020.5.14

  Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenyl-pyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.