N¹,N¹-diethyl-N⁴-1,5-naphthyridin-4-ylpentane-1,4-diamine | 5423-93-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N¹,N¹-diethyl-N⁴-1,5-naphthyridin-4-ylpentane-1,4-diamine
• 英文别名: N⁴,N⁴-diethyl-1-methyl-N¹-[1,5]naphthyridin-4-yl-butanediyldiamine；N⁴,N⁴-Diaethyl-1-methyl-N¹-[1,5]naphthyridin-4-yl-butandiyldiamin；1-N,1-N-diethyl-4-N-(1,5-naphthyridin-4-yl)pentane-1,4-diamine
• CAS: 5423-93-8
• 化学式: C₁₇H₂₆N₄
• 分子量: 286.42
• InChiKey: HFZCIGRYYOVLQK-UHFFFAOYSA-N

物化性质

• 沸点：
  145-148 °C(Press: 0.004 Torr)
• 密度：
  1.064±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  41
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-羟基-1,5-萘啶 在 N-甲基吡咯烷酮 、 三氯氧磷 作用下， 反应 2.25h， 生成 N¹,N¹-diethyl-N⁴-1,5-naphthyridin-4-ylpentane-1,4-diamine
  参考文献：
  名称：

  Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action

  摘要：

  Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.10.061

文献信息

• Synthesis of Antimalarials. VI.¹ Synthesis of Certain 1,5- and 1,8-Naphthyridine Derivatives²
  作者：Joe T. Adams、Charles K. Bradsher、David S. Breslow、S. Thomas Amore、Charles R. Hauser

  DOI：10.1021/ja01211a064

  日期：1946.7
• Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action
  作者：Života Selaković、Julie P. Tran、Krishna P. Kota、Marija Lazić、Cary Retterer、Robert Besch、Rekha G. Panchal、Veronica Soloveva、Vantongreen A. Sean、Wells B. Jay、Aleksandar Pavić、Tatjana Verbić、Branka Vasiljević、Kathleen Kuehl、Allen J. Duplantier、Sina Bavari、Rajini Mudhasani、Bogdan A. Šolaja

  DOI：10.1016/j.ejmech.2018.10.061

  日期：2019.1

  Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease. (C) 2018 Elsevier Masson SAS. All rights reserved.