N-{3-[(3,5-dimethylphenyl)sulfonyl]-5-chloro-1H-indole-2-carbonyl}-D,L-alanine ethyl ester | 742106-24-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-{3-[(3,5-dimethylphenyl)sulfonyl]-5-chloro-1H-indole-2-carbonyl}-D,L-alanine ethyl ester
• 英文别名: ethyl 2-[[5-chloro-3-(3,5-dimethylphenyl)sulfonyl-1H-indole-2-carbonyl]amino]propanoate
• CAS: 742106-24-7
• 化学式: C₂₂H₂₃ClN₂O₅S
• 分子量: 462.954
• InChiKey: JOERKMKTLJRVLZ-UHFFFAOYSA-N

物化性质

• 沸点：
  712.1±60.0 °C(Predicted)
• 密度：
  1.342±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-{3-[(3,5-dimethylphenyl)sulfonyl]-5-chloro-1H-indole-2-carbonyl}-D,L-alanine ethyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 以97%的产率得到N-{3-[(3,5-dimethylphenyl)sulfonyl]-5-chloro-1H-indole-2-carbonyl}-D,L-alanine
  参考文献：
  名称：

  磺酰吲哚羧酰胺（L-737,126）的简单，短肽衍生物在体外对HIV-1野生型和携带非核苷类逆转录酶抑制剂耐药突变的变体具有活性。

  摘要：

  通过在L-737,126的苯磺酰基部分的3和5位上引入两个甲基并将1至3个甘氨酰胺/丙氨酰胺单元与其羧基酰胺偶联，可以获得对NNRTI抗性突变体有活性的非核苷逆转录酶抑制剂（NNRTIs）。功能。在基于细胞的测定中，新衍生物显示出对HIV-1野生型和NNRTI耐药突变体[Y181C，K103N-Y181C和对依非韦伦高度耐药的三重突变体（K103R，V179D，P225H）的活性优于父本的活性。吲哚衍生物1。

  DOI：

  10.1021/jm031147e
• 作为产物：
  描述：

  1-(3,5-dimethylphenylthio)pyrrolidine-2,5-dione 在 lithium hydroxide 、 三氟化硼乙醚 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 101.0h， 生成 N-{3-[(3,5-dimethylphenyl)sulfonyl]-5-chloro-1H-indole-2-carbonyl}-D,L-alanine ethyl ester
  参考文献：
  名称：

  磺酰吲哚羧酰胺（L-737,126）的简单，短肽衍生物在体外对HIV-1野生型和携带非核苷类逆转录酶抑制剂耐药突变的变体具有活性。

  摘要：

  通过在L-737,126的苯磺酰基部分的3和5位上引入两个甲基并将1至3个甘氨酰胺/丙氨酰胺单元与其羧基酰胺偶联，可以获得对NNRTI抗性突变体有活性的非核苷逆转录酶抑制剂（NNRTIs）。功能。在基于细胞的测定中，新衍生物显示出对HIV-1野生型和NNRTI耐药突变体[Y181C，K103N-Y181C和对依非韦伦高度耐药的三重突变体（K103R，V179D，P225H）的活性优于父本的活性。吲哚衍生物1。

  DOI：

  10.1021/jm031147e

文献信息

• High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme
  作者：Reynel Cancio、Romano Silvestri、Rino Ragno、Marino Artico、Gabriella De Martino、Giuseppe La Regina、Emmanuele Crespan、Samantha Zanoli、Ulrich Hübscher、Silvio Spadari、Giovanni Maga

  DOI：10.1128/aac.49.11.4546-4554.2005

  日期：2005.11

  Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

  摘要 吲哚基芳基砜（Indolyl aryl sulfone，IAS）非核苷抑制剂已被证明能有效抑制野生型和耐药型人类免疫缺陷病毒 1 型（HIV-1）的生长，但其确切的作用机制尚未阐明。在此，我们描述了某些 IAS 衍生物对 HIV-1 逆转录酶（RT）的抑制机制。我们的研究结果表明，根据在 IAS 共同药理结构中引入的取代，这些化合物可以对不同的酶-底物复合物产生选择性作用。此外，我们还证明了这种选择性的分子基础是药物与反应途径上特定酶形式的结合率不同。通过比较不同化合物对野生型 RT 和对非核苷类逆转录酶抑制剂有抗性的突变体 Lys103Asn 的活性，我们可以根据它们的作用机制，假设设计出可以克服 Lys103Asn 突变所造成的立体障碍的药物的原理。
• Indolylarylsulfones Bearing Natural and Unnatural Amino Acids. Discovery of Potent Inhibitors of HIV-1 Non-Nucleoside Wild Type and Resistant Mutant Strains Reverse Transcriptase and Coxsackie B4 Virus
  作者：Francesco Piscitelli、Antonio Coluccia、Andrea Brancale、Giuseppe La Regina、Anna Sansone、Cesare Giordano、Jan Balzarini、Giovanni Maga、Samantha Zanoli、Alberta Samuele、Roberto Cirilli、Francesco La Torre、Antonio Lavecchia、Ettore Novellino、Romano Silvestri

  DOI：10.1021/jm801470b

  日期：2009.4.9

  New potent indolylarylsulfone (IAS) HIV-I NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 mu M) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.
• Simple, Short Peptide Derivatives of a Sulfonylindolecarboxamide (L-737,126) Active in Vitro against HIV-1 Wild Type and Variants Carrying Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations
  作者：Romano Silvestri、Marino Artico、Gabriella De Martino、Giuseppe La Regina、Roberta Loddo、Massimiliano La Colla、Paolo La Colla

  DOI：10.1021/jm031147e

  日期：2004.7.1

  Non-nucleoside reverse transcriptase inhibitors (NNRTIs) active against NNRTI-resistant mutants were obtained by introducing two methyl groups at positions 3 and 5 of the benzenesulfonyl moiety of L-737,126 (1) and coupling one to three glycinamide/alaninamide units to its carboxyamide function. In cell-based assays, the new derivatives showed activities against HIV-1 wild type and NNRTI-resistant

  通过在L-737,126的苯磺酰基部分的3和5位上引入两个甲基并将1至3个甘氨酰胺/丙氨酰胺单元与其羧基酰胺偶联，可以获得对NNRTI抗性突变体有活性的非核苷逆转录酶抑制剂（NNRTIs）。功能。在基于细胞的测定中，新衍生物显示出对HIV-1野生型和NNRTI耐药突变体[Y181C，K103N-Y181C和对依非韦伦高度耐药的三重突变体（K103R，V179D，P225H）的活性优于父本的活性。吲哚衍生物1。