N-[(1S)-1-carbamoyl-3-methyl-butyl]-2-[[2-[[(1S)-1-carbamoyl-3-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzamide | 219309-96-3

• 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-[(1S)-1-carbamoyl-3-methyl-butyl]-2-[[2-[[(1S)-1-carbamoyl-3-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzamide
• 英文别名: N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]-2-[[2-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]carbamoyl]phenyl]disulfanyl]benzamide
• CAS: 219309-96-3
• 化学式: C₂₆H₃₄N₄O₄S₂
• 分子量: 530.712
• InChiKey: VXMGIILQPVIYCB-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  195
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[(1S)-1-carbamoyl-3-methyl-butyl]-2-[[2-[[(1S)-1-carbamoyl-3-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzamide 在 tris(carboxyethyl)phosphine hydrochloride 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-((S)-1-Carbamoyl-3-methyl-butyl)-2-mercapto-benzamide
  参考文献：
  名称：

  Synthesis and Biological Properties of Amino Acid Amide Ligand-Based Pyridinioalkanoyl Thioesters as Anti-HIV Agents

  摘要：

  Hyper-mutable retroviruses such as HIV can become rapidly resistant to drugs used to treat infection, Strategies for coping with drug-resistant strains of virus include combination therapies. using viral protease and reverse transcriptase inhibitors. Another approach is the development of antiviral agents that attack mutationally nonpermissive targets that have functions essential for viral replication. Thus, the highly conserved nucleocapsid protein. NCp7, was chosen as a prime target in our search for novel anti-HIV agents that can overcome the problem of viral drug resistance. Recently, we reported (J. Med. Chem. 1999 42, 67) a novel chemotype, the pyridinioalkanoyl thioesters (PATEs), based on 2-mercaptobenzamides as the thiol component and having its amide nitrogen substituted with various phenylsulfonyl moieties. These compounds were identified as relatively nontoxic anti-HIV agents in the XTT cytoprotection assay. In this study. we wish to report a separate genre of active PATEs wherein the thiol component consists of an N-2-mercaptobenzoyl-amino acid derivative. Active derivatives (EC50 < 10 muM) reported herein were confined to amino acid primary amides or methyl amides having side chains no larger than isobutyl. Amino acids terminating in free carboxyl or carboxylic acid ester groups were mostly inactive. Selected compounds were shown to be active on chronically infected CEM/SK-1, TNFalpha-induced U1. ACH-2 cells and virucidal on cell-free virus, latently infected U I cells and acutely infected primary peripheral blood mononuclear cells (PBMCs). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00392-3
• 作为产物：
  描述：

  2, 2'-二硫代二苯甲酸 在 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 4.0h， 生成 N-[(1S)-1-carbamoyl-3-methyl-butyl]-2-[[2-[[(1S)-1-carbamoyl-3-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzamide
  参考文献：
  名称：

  Optimization of unique, uncharged thioesters as inhibitors of HIV replication

  摘要：

  A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercapto-benzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human Serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNFalpha-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC50 values in the 80-100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.09.032

文献信息

• 2,2′-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: synthesis and structure–activity relationship
  作者：J.V.N Vara Prasad、Joseph A Loo、Frederick E Boyer、Michael A Stier、Rocco D Gogliotti、William J Turner、Patricia J Harvey、Melissa R Kramer、David P Mack、Jefferey D Scholten、Stephen J Gracheck、John M Domagala

  DOI：10.1016/s0968-0896(98)00118-7

  日期：1998.10

  2'-dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the alpha-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from beta- and gamma-amino

  含有高度保守的逆转录病毒锌指的核衣壳蛋白（NCp7）在人类免疫缺陷病毒（HIV）生命周期的早期和晚期都是必不可少的，并且是AIDS治疗的新目标。HIV-1 NCp7是基本的55个氨基酸氨基酸蛋白，在两侧各含两个C（X）2C（X）4H（X）4C基序锌指。先前已报道2,2'-二硫代双苯甲酰胺从这些NCp7锌指中释放锌，并抑制HIV复制。具体而言，衍生自简单氨基酸的2,2'-二硫代双苯甲酰胺显示出良好的抗病毒活性。苯并异噻唑酮3（2的环状衍生物）被选为临床试验中的艾滋病治疗剂。本文中我们报告了2,2'的合成和抗病毒活性，包括治疗指数 衍生自α-，β-和γ-氨基酸的β-二硫代双苯甲酰胺。电喷雾电离质谱法用于研究这些化合物的锌喷射活性。在α-氨基酸衍生的2,2'-二硫代双苯甲酰胺中，发现含有烷基侧链的类似物具有良好的治疗指数，具有抗病毒活性。发现衍生自β-和γ-氨基酸的2,2'-二硫代双苯甲酰胺比α
• Synthesis and Biological Properties of Amino Acid Amide Ligand-Based Pyridinioalkanoyl Thioesters as Anti-HIV Agents
  作者：Yongsheng Song、Atul Goel、Venkatesha Basrur、Paula E.A Roberts、Judy A Mikovits、John K Inman、Jim A Turpin、William G Rice、Ettore Appella

  DOI：10.1016/s0968-0896(01)00392-3

  日期：2002.5

  Hyper-mutable retroviruses such as HIV can become rapidly resistant to drugs used to treat infection, Strategies for coping with drug-resistant strains of virus include combination therapies. using viral protease and reverse transcriptase inhibitors. Another approach is the development of antiviral agents that attack mutationally nonpermissive targets that have functions essential for viral replication. Thus, the highly conserved nucleocapsid protein. NCp7, was chosen as a prime target in our search for novel anti-HIV agents that can overcome the problem of viral drug resistance. Recently, we reported (J. Med. Chem. 1999 42, 67) a novel chemotype, the pyridinioalkanoyl thioesters (PATEs), based on 2-mercaptobenzamides as the thiol component and having its amide nitrogen substituted with various phenylsulfonyl moieties. These compounds were identified as relatively nontoxic anti-HIV agents in the XTT cytoprotection assay. In this study. we wish to report a separate genre of active PATEs wherein the thiol component consists of an N-2-mercaptobenzoyl-amino acid derivative. Active derivatives (EC50 < 10 muM) reported herein were confined to amino acid primary amides or methyl amides having side chains no larger than isobutyl. Amino acids terminating in free carboxyl or carboxylic acid ester groups were mostly inactive. Selected compounds were shown to be active on chronically infected CEM/SK-1, TNFalpha-induced U1. ACH-2 cells and virucidal on cell-free virus, latently infected U I cells and acutely infected primary peripheral blood mononuclear cells (PBMCs). (C) 2002 Elsevier Science Ltd. All rights reserved.
• Optimization of unique, uncharged thioesters as inhibitors of HIV replication
  作者：Pratibha Srivastava、Marco Schito、Rasem J. Fattah、Toshiaki Hara、Tracy Hartman、Robert W. Buckheit、Jim A. Turpin、John K. Inman、Ettore Appella

  DOI：10.1016/j.bmc.2004.09.032

  日期：2004.12

  A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercapto-benzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human Serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNFalpha-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC50 values in the 80-100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides. (C) 2004 Elsevier Ltd. All rights reserved.