8-bromo-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并吡啶类
• 英文名称: 8-bromo-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine
• 英文别名: 2-(Benzenesulfonylmethyl)-8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine；2-(benzenesulfonylmethyl)-8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine
• 化学式: C₁₄H₉BrClN₃O₄S
• 分子量: 430.666
• InChiKey: MXNNWAYMTJJJIP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  106
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-bromo-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine 在 铁粉 、 溶剂黄146 作用下， 反应 0.5h， 以75%的产率得到
  参考文献：
  名称：

  8-炔基-3-硝基咪唑并吡啶显示出对两种T都有力的抗锥虫活性。布鲁西和克鲁兹。

  摘要：

  在3-硝基咪唑并[1,2- a ]吡啶系列中，在先前确定的药效基团的位置8进行了抗动素体药物代谢研究。通过Sonogashira交叉偶联反应合成了20个带有炔基的原始衍生物，并在体外进行了测试，突出了3种有效的（40 nM≤EC 50血流形式≤70 nM）和选择性（500≤SI≤1800）抗T.布氏锥虫分子（19，21和22），在具有四个参考药物比较。在这些命中分子中，化合物19也显示出相同水平的抗克鲁氏锥虫活性（EC 50amastigotes = 1.2μM）分别为苯硝唑和fexinidazole。的体外彗星试验表明，硝基芳族衍生物19是没有遗传毒性。它显示出较低的氧化还原电位值（-0.68 V / NHE），并且在利什曼原虫和锥虫中均被1型氮还原酶生物激活。SAR研究表明，当羟基位于炔烃三键的β位时，醇功能可改善水溶性，同时保持良好的活性和低细胞毒性。还针对体外药代动力学数据对命中化

  DOI：

  10.1016/j.ejmech.2020.112558
• 作为产物：
  描述：

  2-氨基-3-溴-5-氯吡啶 在 sodium azide 、 Eaton's reagent 、 硫酸 、 硝酸 、 sodium hydride 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 5.75h， 生成 8-bromo-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine
  参考文献：
  名称：

  提高 3-硝基咪唑并 [1,2-a] 吡啶抗利什曼原虫药效团的水溶性和体外药代动力学特性

  摘要：

  通过合成 22 种新衍生物，对咪唑并 [1,2- a ] 吡啶环的第 2 位和第 8 位进行了抗利什曼氏菌构效关系 (SAR) 研究。在杜氏利什曼原虫和婴儿利什曼原虫的前鞭毛体和无菌无鞭毛体阶段进行筛选后，针对婴儿利什曼原虫的细胞内无鞭毛体阶段测试了最佳化合物，并评估了它们的体外理化和药代动力学特性，从而发现了一种新的antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2- a ]pyridine hit。它对 HepG2 和 THP1 细胞系 (CC 50> 100 µM) 与对L. infantum细胞内无鞭毛体阶段的良好活性相关（EC 50 = 3.7 µM对比米替福新和非昔硝唑的 0.4 和 15.9 µM，用作抗利什曼氏动物药物参考）

  DOI：

  10.3390/ph15080998

文献信息

• Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
  作者：Cyril Fersing、Clotilde Boudot、Romain Paoli-Lombardo、Nicolas Primas、Emilie Pinault、Sébastien Hutter、Caroline Castera-Ducros、Youssef Kabri、Julien Pedron、Sandra Bourgeade-Delmas、Alix Sournia-Saquet、Jean-Luc Stigliani、Alexis Valentin、Amaya Azqueta、Damián Muruzabal、Alexandre Destere、Susan Wyllie、Alan H. Fairlamb、Sophie Corvaisier、Marc Since、Aurélie Malzert-Fréon、Carole Di Giorgio、Pascal Rathelot、Nadine Azas、Bertrand Courtioux、Patrice Vanelle、Pierre Verhaeghe

  DOI：10.1016/j.ejmech.2020.112668

  日期：2020.11

  synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic

  为了研究抗运动型3-硝基咪唑并[1,2- a ]吡啶的药效团，通过合成26种原始衍生物并对其在利什曼原虫和布鲁氏锥虫中的体外评价进行了结构-活性关系研究。这项SAR研究表明，抗锥虫药效团比抗疟药药团的限制性更小，并突出显示了咪唑并吡啶环的2、6和8位为关键调节点。与该系列中以前的命中分子相比，没有一种合成的化合物能提高抗疟疾活性。不过，化合物8是该系列中最好的抗胰锥虫分子（EC 50 = 17 nM，SI = 2650＆E°= -0.6 V），不仅比所有参考药物和该系列中以前的命中分子更有活性，而且还表现出改善的水溶性和更好的体外药代动力学特性：良好的微粒体稳定性（T 1/2  > 40分钟），根据PAMPA分析的中等白蛋白结合率（77％）和穿过血脑屏障的中等渗透率。此外，微核和彗星试验均表明硝基芳香分子8在体外没有遗传毒性。证明了分子8的生物活化是由T.b.进行的。布氏1型硝基还原酶，以
• 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases
  作者：Cyril Fersing、Clotilde Boudot、Julien Pedron、Sébastien Hutter、Nicolas Primas、Caroline Castera-Ducros、Sandra Bourgeade-Delmas、Alix Sournia-Saquet、Alain Moreau、Anita Cohen、Jean-Luc Stigliani、Geneviève Pratviel、Maxime D. Crozet、Susan Wyllie、Alan Fairlamb、Alexis Valentin、Pascal Rathelot、Nadine Azas、Bertrand Courtioux、Pierre Verhaeghe、Patrice Vanelle

  DOI：10.1016/j.ejmech.2018.07.064

  日期：2018.9

  Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 mu M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 mu M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) and selective (SI = >313 to 550) molecules toward T brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 mu M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTRI), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V. Crown Copyright (C) 2018 Published by Elsevier Masson SAS. All rights reserved.
• Nongenotoxic 3-Nitroimidazo[1,2-<i>a</i>]pyridines Are NTR1 Substrates That Display Potent <i>in Vitro</i> Antileishmanial Activity
  作者：Cyril Fersing、Louise Basmaciyan、Clotilde Boudot、Julien Pedron、Sébastien Hutter、Anita Cohen、Caroline Castera-Ducros、Nicolas Primas、Michèle Laget、Magali Casanova、Sandra Bourgeade-Delmas、Mélanie Piednoel、Alix Sournia-Saquet、Valère Belle Mbou、Bertrand Courtioux、Élisa Boutet-Robinet、Marc Since、Rachel Milne、Susan Wyllie、Alan H. Fairlamb、Alexis Valentin、Pascal Rathelot、Pierre Verhaeghe、Patrice Vanelle、Nadine Azas

  DOI：10.1021/acsmedchemlett.8b00347

  日期：2019.1.10

  Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.
• 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi
  作者：Cyril Fersing、Clotilde Boudot、Caroline Castera-Ducros、Emilie Pinault、Sébastien Hutter、Romain Paoli-Lombardo、Nicolas Primas、Julien Pedron、Line Seguy、Sandra Bourgeade-Delmas、Alix Sournia-Saquet、Jean-Luc Stigliani、Jean-Yves Brossas、Luc Paris、Alexis Valentin、Susan Wyllie、Alan H. Fairlamb、Élisa Boutet-Robinet、Sophie Corvaisier、Marc Since、Aurélie Malzert-Fréon、Alexandre Destere、Dominique Mazier、Pascal Rathelot、Bertrand Courtioux、Nadine Azas、Pierre Verhaeghe、Patrice Vanelle

  DOI：10.1016/j.ejmech.2020.112558

  日期：2020.9

  that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and

  在3-硝基咪唑并[1,2- a ]吡啶系列中，在先前确定的药效基团的位置8进行了抗动素体药物代谢研究。通过Sonogashira交叉偶联反应合成了20个带有炔基的原始衍生物，并在体外进行了测试，突出了3种有效的（40 nM≤EC 50血流形式≤70 nM）和选择性（500≤SI≤1800）抗T.布氏锥虫分子（19，21和22），在具有四个参考药物比较。在这些命中分子中，化合物19也显示出相同水平的抗克鲁氏锥虫活性（EC 50amastigotes = 1.2μM）分别为苯硝唑和fexinidazole。的体外彗星试验表明，硝基芳族衍生物19是没有遗传毒性。它显示出较低的氧化还原电位值（-0.68 V / NHE），并且在利什曼原虫和锥虫中均被1型氮还原酶生物激活。SAR研究表明，当羟基位于炔烃三键的β位时，醇功能可改善水溶性，同时保持良好的活性和低细胞毒性。还针对体外药代动力学数据对命中化
• Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore
  作者：Romain Paoli-Lombardo、Nicolas Primas、Sandra Bourgeade-Delmas、Sébastien Hutter、Alix Sournia-Saquet、Clotilde Boudot、Emilie Brenot、Caroline Castera-Ducros、Sophie Corvaisier、Marc Since、Aurélie Malzert-Fréon、Bertrand Courtioux、Alexis Valentin、Pierre Verhaeghe、Nadine Azas、Pascal Rathelot、Patrice Vanelle

  DOI：10.3390/ph15080998

  日期：——

  their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus

  通过合成 22 种新衍生物，对咪唑并 [1,2- a ] 吡啶环的第 2 位和第 8 位进行了抗利什曼氏菌构效关系 (SAR) 研究。在杜氏利什曼原虫和婴儿利什曼原虫的前鞭毛体和无菌无鞭毛体阶段进行筛选后，针对婴儿利什曼原虫的细胞内无鞭毛体阶段测试了最佳化合物，并评估了它们的体外理化和药代动力学特性，从而发现了一种新的antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2- a ]pyridine hit。它对 HepG2 和 THP1 细胞系 (CC 50> 100 µM) 与对L. infantum细胞内无鞭毛体阶段的良好活性相关（EC 50 = 3.7 µM对比米替福新和非昔硝唑的 0.4 和 15.9 µM，用作抗利什曼氏动物药物参考）