1-(4-fluorobenzyl)-2-(4-(4-methoxyphenethyl)-piperazin-1-yl)-1H-benzo[d]imidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-(4-fluorobenzyl)-2-(4-(4-methoxyphenethyl)-piperazin-1-yl)-1H-benzo[d]imidazole
• 英文别名: 1-[(4-Fluorophenyl)methyl]-2-[4-[2-(4-methoxyphenyl)ethyl]piperazin-1-yl]benzimidazole；1-[(4-fluorophenyl)methyl]-2-[4-[2-(4-methoxyphenyl)ethyl]piperazin-1-yl]benzimidazole
• 化学式: C₂₇H₂₉FN₄O
• 分子量: 444.552
• InChiKey: LSTRXUWGNOMUBF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  33.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对甲氧基苯乙醇 在 戴斯-马丁氧化剂 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 21.0h， 生成 1-(4-fluorobenzyl)-2-(4-(4-methoxyphenethyl)-piperazin-1-yl)-1H-benzo[d]imidazole
  参考文献：
  名称：

  Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds

  摘要：

  Astemizole is a H-1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.10.004

文献信息

• Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
  作者：Malkeet Kumar、John Okombo、Dickson Mambwe、Dale Taylor、Nina Lawrence、Janette Reader、Mariëtte van der Watt、Diana Fontinha、Margarida Sanches-Vaz、Belinda C. Bezuidenhout、Sonja B. Lauterbach、Dale Liebenberg、Lyn-Marie Birkholtz、Theresa L. Coetzer、Miguel Prudêncio、Timothy J. Egan、Sergio Wittlin、Kelly Chibale

  DOI：10.1021/acsinfecdis.8b00272

  日期：2019.2.8

  analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their

  利用药物重新定位方法衍生化阿司咪唑（AST），这是一种抗组胺药，其抗疟活性先前已在高通量筛选中确定。通过评估寄生虫的无性血液，肝脏和性配子分裂阶段，检查了其后类似物对疟原虫的生命周期的多阶段活性潜能。另外，对先前报道的血红素解毒对化合物作用方式的贡献进行了研究。17种衍生物中的10种对氯喹（CQ）敏感的恶性疟原虫NF54（PfNF54）菌株显示半数最大抑制浓度（IC50s）<0.1μM，同时对多药耐药菌株PfK1保持亚微摩尔效价，多数显示低与CQ交叉耐药的可能性。测试了选定的类似物（PfNF54-IC50 <0.1μM）对中国仓鼠卵巢（CHO）细胞的细胞毒性，发现其具有高度选择性（选择性指数> 100）。AST及其类似物针对配子体细胞的筛选显示了其对晚期恶性疟原虫配体细胞的中等活性（IC50：1-5μM），而对伯氏疟原虫肝阶段活性的评估则鉴定出一种化合物（3）的活性提高了3倍活性要比母体A
• Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
  作者：Junjun Tian、Leen Vandermosten、Steve Peigneur、Lien Moreels、Jef Rozenski、Jan Tytgat、Piet Herdewijn、Philippe E. Van den Steen、Steven De Jonghe

  DOI：10.1016/j.bmc.2017.10.004

  日期：2017.12

  Astemizole is a H-1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials. (C) 2017 Elsevier Ltd. All rights reserved.