2-hydroxy-4-oxo-4-o-tolylbut-2-enoic acid ethyl ester | 1260599-08-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-hydroxy-4-oxo-4-o-tolylbut-2-enoic acid ethyl ester
• CAS: 1260599-08-3
• 化学式: C₁₃H₁₄O₄
• 分子量: 234.252
• InChiKey: JPMDRTPSCQBGIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.18
• 重原子数：
  17.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  63.6
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-hydroxy-4-oxo-4-o-tolylbut-2-enoic acid ethyl ester 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 0.75h， 以71%的产率得到2-hydroxy-4-oxo-4-o-tolylbut-2-enoic acid
  参考文献：
  名称：

  Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

  摘要：

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.08.028
• 作为产物：
  描述：

  草酸二乙酯 、 1-甲基苯基乙酮 在 sodium 作用下， 以 乙醇 为溶剂， 生成 2-hydroxy-4-oxo-4-o-tolylbut-2-enoic acid ethyl ester
  参考文献：
  名称：

  Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis

  摘要：

  This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 mu g/mL (0.37-0.75 mu M) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.

  DOI：

  10.1016/j.bmcl.2019.07.025

文献信息

• “On water” synthesis of N-unsubstituted pyrazoles: semicarbazide hydrochloride as an alternative to hydrazine for preparation of pyrazole-3-carboxylate derivatives and 3,5-disubstituted pyrazoles
  作者：Violeta Marković、Milan D. Joksović

  DOI：10.1039/c4gc02028f

  日期：——

  A green, simple and highly efficient method for the synthesis of pyrazole-3-carboxylates and 3,5-disubstituted pyrazoles by cyclization of 4-aryl(hetaryl, alkyl)-2,4-diketoesters and 1,3-diketones with semicarbazide hydrochloride under “on water” conditions has been developed. This method also does not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals.

  一种绿色，简单且高效的方法，通过用氨基脲盐酸盐将4-芳基（杂芳基，烷基）-2,4-二酮酸酯和1,3-二酮环化，合成吡唑-3-羧酸酯和3,5-二取代的吡唑在“水上”条件下已经开发出来。该方法也不需要毒性肼和产物纯化，从而消除了对有毒液体化学物质的使用。
• 1-(6 MEMBERS AZO-HETEROCYCLIC)-PYRROLIN-2-ONE COMPOUNDS AS INHIBITORS OF HEPATITIS C NS5B POLYMERASE, THE PHARAMACEUTICAL COMPOSITION THEREOF AND THEIR THERAPEUTIC USE
  申请人：Berecibar Amaya

  公开号：US20120128630A1

  公开（公告）日：2012-05-24

  The present invention concerns a 1-(6 members azo-heterocyclic)-pyrrolin-2-one compound of the following formula I or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof: the pharmaceutical composition thereof and their therapeutic use as inhibitors of Hepatitis C NS5B polymerase.

  本发明涉及以下公式I的1-(6成员偶氮杂环)-吡咯烷-2-酮化合物或其盐、溶剂化物、互变异构体、同位素、对映异构体或其混合物：其药物组合物及其作为丙型肝炎NS5B聚合酶抑制剂的治疗用途。
• Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis
  作者：Daniele Zampieri、Maria Grazia Mamolo、Julia Filingeri、Sara Fortuna、Alessandro De Logu、Adriana Sanna、Davide Zanon

  DOI：10.1016/j.bmcl.2019.07.025

  日期：2019.9

  This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 mu g/mL (0.37-0.75 mu M) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.
• Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition
  作者：Aaditya Bhatt、K.R. Gurukumar、Amartya Basu、Maulik R. Patel、Neerja Kaushik-Basu、Tanaji T. Talele

  DOI：10.1016/j.ejmech.2011.08.028

  日期：2011.10

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.