(2S,3S,5S)-2,5-bis[N-[(3-hydroxyphenyl)carbonyl]amino]-3,4-dihydroxy-1,6-diphenyl hexane

• 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: (2S,3S,5S)-2,5-bis[N-[(3-hydroxyphenyl)carbonyl]amino]-3,4-dihydroxy-1,6-diphenyl hexane
• 英文别名: 3-hydroxy-N-[(2S,4S,5S)-4-hydroxy-5-[(3-hydroxybenzoyl)amino]-1,6-diphenylhexan-2-yl]benzamide
• 化学式: C₃₂H₃₂N₂O₅
• 分子量: 524.616
• InChiKey: BBSGSVSTLAGWDW-NSGJQZOKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  119
• 氢给体数：
  5
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  间羟基苯甲酸 、 SSS-2,5-diamino-1,6-diphenyl-3-hexanol 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 (2S,3S,5S)-2,5-bis[N-[(3-hydroxyphenyl)carbonyl]amino]-3,4-dihydroxy-1,6-diphenyl hexane
  参考文献：
  名称：

  Structure-based design of achiral, nonpeptidic hydroxybenzamide as a novel P2/P2′ replacement for the symmetry-based HIV protease inhibitors

  摘要：

  A combination of structure-activity studies, kinetic analysis, X-ray crystallographic analysis, and modeling were employed in the design of a novel series of HIV-1 protease (HIV PR) inhibitors. The crystal structure of a complex of HIV PR with SRSS-2,5-bis[N-(tert-butyloxycarbonyl)amino]-3,4-dihydroxy-1,6-diphenylhexane (1) delineated a crucial water-mediated hydrogen bond between the tert-butyloxy group of the inhibitor and the amide hydrogen of Asp29 of the enzyme. Achiral, nonpeptidic 2-hydroxyphenylacetamide and 9-hydroxybenzamide groups were modeled as novel P2/P2' ligands to replace the crystallographic water molecules and to provide direct interactions with the NH groups of the Asp29/129 residues. Indeed, the symmetry-based inhibitors 7 and 19, possessing 3-hydroxy and 3-aminobenzamide, respectively, as a P2/P2' ligand, were potent inhibitors of HIV PR. The benzamides were superior in potency to the phenylacetamides and have four fewer rotatable bonds. An X-ray crystal structure of the HIV PR/7 complex at 2.1 Angstrom resolution revealed an asymmetric mode of binding, in which the 3-hydroxy group of the benzamide ring makes the predicted interaction with the backbone NH of Asp29 on one side of the active site only. An unexpected hydrogen bond with the Gly148 carbonyl group, resulting from rotation of the aromatic ring out of the amide plane, was observed on the other side. The inhibitory potencies of the benzamide compounds were found to be sensitive to the nature and position of substituents on the benzamide ring, and can be rationalized on the basis of the structure of the HIV PR/7 complex. These results partly confirm our initial hypothesis and suggest that optimal inhibitor designs should satisfy a requirement for providing polar interactions with Asp29 NH, and should minimize the conformational entropy loss on binding by reducing the number of freely rotatable bonds in inhibitors. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0968-0896(96)00140-x

文献信息

• 2,5-DIAMINO-3,4-DISUBSTITUTED-1,6-DIPHENYLHEXANE ISOSTERES COMPRISING BENZAMIDE, SULFONAMIDE AND ANTHRANILAMIDE SUBUNITS AND METHODS OF USING SAME
  申请人：THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, Department of Health and Human Services

  公开号：EP0801640B1

  公开（公告）日：2003-03-26
• Structure-based design of achiral, nonpeptidic hydroxybenzamide as a novel P2/P2′ replacement for the symmetry-based HIV protease inhibitors
  作者：Ramnarayan S. Randad、Lucyna Lubkowska、Abelardo M. Silva、Diego M.A. Guerin、Sergei V. Gulnik、Betty Yu、John W. Erickson

  DOI：10.1016/0968-0896(96)00140-x

  日期：1996.9

  A combination of structure-activity studies, kinetic analysis, X-ray crystallographic analysis, and modeling were employed in the design of a novel series of HIV-1 protease (HIV PR) inhibitors. The crystal structure of a complex of HIV PR with SRSS-2,5-bis[N-(tert-butyloxycarbonyl)amino]-3,4-dihydroxy-1,6-diphenylhexane (1) delineated a crucial water-mediated hydrogen bond between the tert-butyloxy group of the inhibitor and the amide hydrogen of Asp29 of the enzyme. Achiral, nonpeptidic 2-hydroxyphenylacetamide and 9-hydroxybenzamide groups were modeled as novel P2/P2' ligands to replace the crystallographic water molecules and to provide direct interactions with the NH groups of the Asp29/129 residues. Indeed, the symmetry-based inhibitors 7 and 19, possessing 3-hydroxy and 3-aminobenzamide, respectively, as a P2/P2' ligand, were potent inhibitors of HIV PR. The benzamides were superior in potency to the phenylacetamides and have four fewer rotatable bonds. An X-ray crystal structure of the HIV PR/7 complex at 2.1 Angstrom resolution revealed an asymmetric mode of binding, in which the 3-hydroxy group of the benzamide ring makes the predicted interaction with the backbone NH of Asp29 on one side of the active site only. An unexpected hydrogen bond with the Gly148 carbonyl group, resulting from rotation of the aromatic ring out of the amide plane, was observed on the other side. The inhibitory potencies of the benzamide compounds were found to be sensitive to the nature and position of substituents on the benzamide ring, and can be rationalized on the basis of the structure of the HIV PR/7 complex. These results partly confirm our initial hypothesis and suggest that optimal inhibitor designs should satisfy a requirement for providing polar interactions with Asp29 NH, and should minimize the conformational entropy loss on binding by reducing the number of freely rotatable bonds in inhibitors. Copyright (C) 1996 Elsevier Science Ltd