5-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid | 131172-61-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 5-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid
• CAS: 131172-61-7
• 化学式: C₁₁H₈ClNO₂
• mdl: MFCD01217348
• 分子量: 221.643
• InChiKey: KIUIWIJLBPLGPN-UHFFFAOYSA-N

物化性质

• 沸点：
  474.5±35.0 °C(Predicted)
• 密度：
  1.407±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  53.1
• 氢给体数：
  2
• 氢受体数：
  2

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  5-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid 在 1,3-二甲基巴比妥酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三苯基膦 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 作用下， 以 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.17h， 生成 5-(4-chlorophenyl)-N-((5-(hydroxymethyl)-4-methylthiazol-2-yl)-(piperidin-2-yl)methyl)-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

  摘要：

  Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NED-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

  DOI：

  10.1021/acs.jmedchem.5b00709
• 作为产物：
  描述：

  1-(4-氯苯基)-乙酮肟 在 吡啶 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 乙醚 、 乙醇 、 水 、 二甲基亚砜 为溶剂， 反应 9.0h， 生成 5-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid
  参考文献：
  名称：

  Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

  摘要：

  Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NED-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

  DOI：

  10.1021/acs.jmedchem.5b00709

文献信息

• General method for the synthesis of 5-arylpyrrole-2-carboxylic acids
  作者：Jesús Ezquerra、Concepción Pedregal、Almudena Rubio、Jesús Valenciano、José Luis García Navio、Julio Alvarez-Builla、Juan José Vaquero

  DOI：10.1016/s0040-4039(00)73741-5

  日期：1993.9

  5-Arylpyrrole-2-carboxylic acids are prepared by DDQ oxidative aromatization of the corresponding ethyl 2-aryl-Δ1-pyrroline-5-carboxylate followed by basic hydrolysis.

  5-芳基吡咯-2-羧酸是由相应的2-芳基- Δ的DDQ氧化芳构化制备1吡咯啉-5-羧酸乙酯，随后碱性水解。
• Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements
  作者：Ildar R. Iusupov、Francesca Curreli、Evgeniy A. Spiridonov、Pavel O. Markov、Shahad Ahmed、Dmitry S. Belov、Ekaterina V. Manasova、Andrea Altieri、Alexander V. Kurkin、Asim K. Debnath

  DOI：10.1016/j.ejmech.2021.113681

  日期：2021.11

  We present the development of alternative scaffolds and validation of their synthetic pathways as a tool for the exploration of new HIV gp120 inhibitors based on the recently discovered inhibitor of this class, NBD-14136. The new synthetic routes were based on isosteric replacements of the amine and acid precursors required for the synthesis of NBD-14136, guided by molecular modeling and chemical feasibility

  我们介绍了替代支架的开发及其合成途径的验证，作为探索基于最近发现的此类抑制剂 NBD-14136 的新型 HIV gp120 抑制剂的工具。新的合成路线基于合成 NBD-14136 所需的胺和酸前体的等排置换，以分子建模和化学可行性分析为指导。为确保这些合成工具和新支架具有进一步探索的潜力，我们最终针对 gp120 抑制测定和细胞活力测定测试了来自每个新设计的支架的少数代表性化合物。
• Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120
  作者：Francesca Curreli、Young Do Kwon、Dmitry S. Belov、Ranjith R. Ramesh、Alexander V. Kurkin、Andrea Altieri、Peter D. Kwong、Asim K. Debnath

  DOI：10.1021/acs.jmedchem.7b00179

  日期：2017.4.13

  entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure–activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist

  为了优化HIV-1进入前导拮抗剂NBD-11021，我们在本研究中提出了60种新类似物的合理设计和合成，并在单周期和多周期感染试验中确定了其抗病毒活性，从而得出了一种新的抗病毒药物。全面的结构－活动关系（SAR）。在针对一大批Env假型病毒的单周期分析中，与先导进入拮抗剂相比，其中两种化合物NBD-14088和NBD-14107在抗病毒活性方面显示出显着改善。相似化合物NBD-14010的X射线结构证实了新设计化合物的结合模式。这些化合物的体外ADMET谱与最有效的附着抑制剂BMS-626529相当，后者的前药目前正在接受III期临床试验。
• Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity
  作者：Francesca Curreli、Dmitry S. Belov、Ranjith R. Ramesh、Naisargi Patel、Andrea Altieri、Alexander V. Kurkin、Asim K. Debnath

  DOI：10.1016/j.bmc.2016.09.057

  日期：2016.11

  Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first

  自从我们首次发现针对HIV-1 gp120的Phe43腔的CD4模仿物NBD-556之后，我们和其他小组在设计具有病毒进入拮抗特性的新CD4模仿物方面取得了长足的进步。在继续努力以取得进一步进展的基础上，我们基于先前报道的病毒进入拮抗剂NBD-11021合成了25种新的类似物。这些化合物首先在基于HIV-1 Env-伪病毒的单周期感染检测以及多周期感染检测中进行测试。这些新化合物中的四个显示出大大提高的抗病毒效力以及细胞毒性。我们选择了两种最好的化合物45A（NBD-14009）和46A（NBD-14010）以针对代表各种临床分离株亚型的51种Env-假型HIV-1进行测试。这些化合物显示出显着的抗病毒效力广度，IC 50低至150 nM。这些化合物还抑制细胞间融合和细胞间HIV-1传播。该研究有望为设计针对HIV-1 gp120的Phe43腔的更有效和更具选择性的HIV-1进入抑制剂铺平道路。
• Synthesis of 5-Arylpyrrole-2-carboxylic Acids as Key Intermediates for NBD Series HIV-1 Entry Inhibitors
  作者：Asim Debnath、Dmitry Belov、Vladimir Ivanov、Francesca Curreli、Alexander Kurkin、Andrea Altieri

  DOI：10.1055/s-0036-1588780

  日期：2017.8

  5-Arylpyrrole-2-carboxylic acids are important key intermediates in the synthesis of HIV-1 entry inhibitors (such as NBD-11021 and NBD-14010). Here we present a general method for the synthesis of some 5-arylpyrrole-2-carboxylic acids in three steps starting from pyrrole. By this method, the compounds could be prepared on gram scale and without chromatographic purification. 5-Arylpyrrole-2-carboxylic acids are important

  摘要 5-芳基吡咯-2-羧酸是合成HIV-1进入抑制剂（例如NBD-11021和NBD-14010）的重要关键中间体。在这里，我们介绍了从吡咯开始的三个步骤中，一些5-芳基吡咯-2-羧酸合成的一般方法。通过这种方法，可以以克为单位制备化合物，而无需色谱纯化。 5-芳基吡咯-2-羧酸是合成HIV-1进入抑制剂（例如NBD-11021和NBD-14010）的重要关键中间体。在这里，我们介绍了从吡咯开始的三个步骤中，一些5-芳基吡咯-2-羧酸合成的一般方法。通过这种方法，可以以克为单位制备化合物，而无需色谱纯化。