1H-indol-2-carboxylic acid [cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-[2-(3,4-dimethoxyphenyl)ethyl]amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1H-indol-2-carboxylic acid [cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-[2-(3,4-dimethoxyphenyl)ethyl]amide
• 英文别名: 1H-indole-2-carboxylic acid [cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-[2-(3,4-dimethoxyphenyl)ethyl]amide；N-[2-(cyclohexylamino)-1-(4-nitrophenyl)-2-oxoethyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-1H-indole-2-carboxamide
• 化学式: C₃₃H₃₆N₄O₆
• 分子量: 584.672
• InChiKey: QBMNXSJPBKIUST-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  吲哚-2-羧酸 、 异氰环已烷 、 对硝基苯甲醛 、 3,4-二甲氧基苯乙胺 以 甲醇 为溶剂， 反应 5.0h， 以41%的产率得到1H-indol-2-carboxylic acid [cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-[2-(3,4-dimethoxyphenyl)ethyl]amide
  参考文献：
  名称：

  SAR study of bisamides as cyclophilin a inhibitors for the development of host-targeting therapy for hepatitis C virus infection

  摘要：

  The therapy of chronic hepatitis C virus infections has significantly improved with the development of directacting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pangenotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for antiHCV treatment.

  DOI：

  10.1016/j.bmc.2020.115679

文献信息

• NOVEL BIS-AMIDE DERIVATIVE AND USE THEREOF
  申请人：UNIVERSITY-INDUSTRY COOPERATION GROUP OF KYUNG HEE UNIVERSITY

  公开号：US20160297751A1

  公开（公告）日：2016-10-13

  The present invention relates to a novel bis-amide derivative compound or a pharmaceutically acceptable salt thereof; a method of preparation thereof; and a pharmaceutical composition for preventing or treating diseases caused by hepatitis C virus infection and health functional food for preventing or ameliorating diseases caused by hepatitis C virus infection, containing the bis-amide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient. The novel bis-amide derivative compound of the present invention, particularly WJCPA-126, specifically binds to the catalytic site of CypA to effectively inhibit the activity of an isomerase, and the duration of the inhibitory effect can be increased because WJCPA-126 binds to CypA with high binding affinity exhibiting a low dissociation rate (K off ). Accordingly, WJCPA-126 has nontoxic and non-immunosuppressive characteristics and can effectively inhibit HCV replication in vitro and in vivo model systems. Additionally, WJCPA-126 reactivates the host interferon response through an increase in the expression of IFN-stimulated genes (ISGs) and the inhibition of interleukin-8 (IL-8) secretion. Therefore, a series of the bis-amide derivatives including WJCPA-126 can be useful as a novel type CypA inhibitor exhibiting antiviral effect.