3-(2-(3(R)-tetrahydrofuranyl)-1-oxoethyl)-4(S)-(phenylmethyl)-2-oxazolidinone | 146255-27-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 3-(2-(3(R)-tetrahydrofuranyl)-1-oxoethyl)-4(S)-(phenylmethyl)-2-oxazolidinone
• 英文别名: (4S)-4-benzyl-3-[2-[(3R)-oxolan-3-yl]acetyl]-1,3-oxazolidin-2-one
• CAS: 146255-27-8
• 化学式: C₁₆H₁₉NO₄
• 分子量: 289.331
• InChiKey: KIGIKGOUMVJQFR-KGLIPLIRSA-N

物化性质

• 沸点：
  476.6±18.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.0
• 重原子数：
  21.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  55.84
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  3-(2-(3(R)-tetrahydrofuranyl)-1-oxoethyl)-4(S)-(phenylmethyl)-2-oxazolidinone 在 palladium on activated charcoal N-甲基吗啉 、 lithium hydroxide 、 2,4,6-三异丙基苯磺酰叠氮化物 、 氢气 、 双(三甲基硅烷基)氨基钾 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.28h， 生成 N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((N-((5-(4-methylpiperazinyl)-6-chloro-2-pyrazinyl)carbonyl)-2(S)-(3(R)-tetrahydrofuranyl)glycinyl)amino)butyl>decahydro-(4aS,8aS) isoquinoline-3(S)-carboxamide
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006
• 作为产物：
  描述：

  (R)-2-(四氢呋喃-3-基)乙酸 在 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.58h， 生成 3-(2-(3(R)-tetrahydrofuranyl)-1-oxoethyl)-4(S)-(phenylmethyl)-2-oxazolidinone
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006

文献信息

• Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine
  作者：Koushi Hidaka、Tooru Kimura、Rajesh Sankaranarayanan、Jun Wang、Keith F. McDaniel、Dale J. Kempf、Masanori Kameoka、Motoyasu Adachi、Ryota Kuroki、Jeffrey-Tri Nguyen、Yoshio Hayashi、Yoshiaki Kiso

  DOI：10.1021/acs.jmedchem.7b01709

  日期：2018.6.28

  The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P-3, P-2, and P-2' moieties. The derivatives with P-2 tetrahydrofur-anylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.
• 3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease
  作者：Wayne J. Thompson、Arun K. Ghosh、M. Katharine Holloway、Hee Yoon Lee、Peter M. Munson、John E. Schwering、Jenny Wai、Paul L. Darke、Joan Zugay

  DOI：10.1021/ja00055a069

  日期：1993.1

  The blockade of the HIV protease has become a major target in the search for an effective therapy for AIDS.1 While many reports of potent HIV-1 inhibitors have appeared recently, the compound Ro 31-8959 remains the least selective for the HIV-1 and HIV-2 proteases.2 This property may result in reduced susceptibility to resistance since these represent the genetically most divergent strains of HIV presently known to exist.