(R)-N-(2-methylallyl)-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide | 1179356-13-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (R)-N-(2-methylallyl)-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
• 英文别名: tert-butyl N-[(2S,3S)-4-[(4R)-5,5-dimethyl-4-(2-methylprop-2-enylcarbamoyl)-1,3-thiazolidin-3-yl]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]carbamate
• CAS: 1179356-13-8
• 化学式: C₂₅H₃₇N₃O₅S
• 分子量: 491.652
• InChiKey: MJWAANPZFCVJBG-SLFFLAALSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-N-(2-methylallyl)-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-N-(2-methylallyl)-3-[(2S,3S)-3-((S)-2-(3-(dimethylamino)phenoxyacetyl)amino-2-((R)-tetrahydrofuran-3-yl)acetyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
  参考文献：
  名称：

  Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.7b01709
• 作为产物：
  描述：

  、 (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-N-(2-methylallyl)-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
  参考文献：
  名称：

  Small-Sized Human Immunodeficiency Virus Type-1 Protease Inhibitors Containing Allophenylnorstatine to Explore the S₂′ Pocket

  摘要：

  A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P-2' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate I (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of all anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity, X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group kit P-2' position revealed hydrophobic interactions with Ala28, Ile84, kind Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.

  DOI：

  10.1021/jm9005115