N-[1-methyl-5-({[1-methyl-5-({[1-methyl-5-({[3-(4-morpholinyl)propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-3-isoquinolinecarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: N-[1-methyl-5-({[1-methyl-5-({[1-methyl-5-({[3-(4-morpholinyl)propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-3-isoquinolinecarboxamide
• 英文别名: N-[1-methyl-5-[[1-methyl-5-[[1-methyl-5-(3-morpholin-4-ylpropylcarbamoyl)pyrrol-3-yl]carbamoyl]pyrrol-3-yl]carbamoyl]pyrrol-3-yl]isoquinoline-3-carboxamide
• 化学式: C₃₅H₃₉N₉O₅
• 分子量: 665.752
• InChiKey: SZLVDTMOAAYYMF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  49
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  157
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  异喹啉-3-甲酸 在 氢氧化钾 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 43.0h， 生成 N-[1-methyl-5-({[1-methyl-5-({[1-methyl-5-({[3-(4-morpholinyl)propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-3-isoquinolinecarboxamide
  参考文献：
  名称：

  DNA Binding Ligands Targeting Drug-Resistant Bacteria:  Structure, Activity, and Pharmacology

  摘要：

  We describe the lead optimization and structure-activity relationship of DNA minor-groove binding ligands, a novel class of antibacterial molecules. These compounds have been shown to target A/T-rich sites within the bacterial genome and, as a result, inhibit DNA replication and RNA transcription. The optimization was focused on N-terminal aromatic heterocycles and C-terminal amines and resulted in compounds with improved in vivo tolerability and excellent in vitro antibacterial potency (MIC greater than or equal to 0.031 mug/mL) against a broad range of Grainpositive pathogens, including drug-resistant strains such as methicillin-resistant Stapylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE). In a first proof-of-concept study, a selected compound (35) showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive S. aureus infection with an ED50 value of 30 mg/kg.

  DOI：

  10.1021/jm030097a

文献信息

• An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics
  作者：Fraser J. Scott、Abedawn I. Khalaf、Federica Giordani、Pui Ee Wong、Sandra Duffy、Michael Barrett、Vicky M. Avery、Colin J. Suckling

  DOI：10.1016/j.ejmech.2016.03.064

  日期：2016.6

  A series of 32, structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activity. (C) 2016 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.orgilicensesiby/4.0/).
• DNA Binding Ligands Targeting Drug-Resistant Bacteria:  Structure, Activity, and Pharmacology
  作者：Jacob A. Kaizerman、Matthew I. Gross、Yigong Ge、Sarah White、Wenhao Hu、Jian-Xin Duan、Eldon E. Baird、Kirk W. Johnson、Richard D. Tanaka、Heinz E. Moser、Roland W. Bürli

  DOI：10.1021/jm030097a

  日期：2003.8.1

  We describe the lead optimization and structure-activity relationship of DNA minor-groove binding ligands, a novel class of antibacterial molecules. These compounds have been shown to target A/T-rich sites within the bacterial genome and, as a result, inhibit DNA replication and RNA transcription. The optimization was focused on N-terminal aromatic heterocycles and C-terminal amines and resulted in compounds with improved in vivo tolerability and excellent in vitro antibacterial potency (MIC greater than or equal to 0.031 mug/mL) against a broad range of Grainpositive pathogens, including drug-resistant strains such as methicillin-resistant Stapylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE). In a first proof-of-concept study, a selected compound (35) showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive S. aureus infection with an ED50 value of 30 mg/kg.