[4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl)phenyl]acetic acid | 909778-31-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: [4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl)phenyl]acetic acid
• 英文别名: [4-(3-methyl-2-ylmethyl-1,4-naphtoquinone)phenyl]-acetic acid；2-[4-[(3-Methyl-1,4-dioxonaphthalen-2-yl)methyl]phenyl]acetic acid
• CAS: 909778-31-0
• 化学式: C₂₀H₁₆O₄
• 分子量: 320.345
• InChiKey: BQPKMVHUIALBPM-UHFFFAOYSA-N

物化性质

• 熔点：
  173 °C
• 沸点：
  540.1±50.0 °C(predicted)
• 密度：
  1.311±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl)phenyl]acetic acid 、 N-(7-chloro-quinolin-4-yl)-N'-isopropyl-ethane-1,2-diamine 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以23.2%的产率得到N-[2-[(7-chloroquinolin-4-yl)amino]ethyl]-2-[4-[(3-methyl-1,4-dioxonaphthalen-2-yl)methyl]phenyl]-N-propan-2-ylacetamide
  参考文献：
  名称：

  Antimalarial Dual Drugs Based on Potent Inhibitors of Glutathione Reductase from Plasmodium falciparum

  摘要：

  Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe-III)protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.

  DOI：

  10.1021/jm7009292
• 作为产物：
  描述：

  甲萘醌 、 1,4-苯二乙酸 在 NH₄S₂O₈ 、 silver nitrate 作用下， 以 水 、 乙腈 为溶剂， 以75.3%的产率得到[4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl)phenyl]acetic acid
  参考文献：
  名称：

  甲萘醌衍生物 6-[2'-(3'-Methyl)-1',4'-naphthoquinolyl] 己酸的氟类似物是谷胱甘肽还原酶的自杀底物。烷基化人类酶的晶体结构†

  摘要：

  谷胱甘肽还原酶是人体细胞和热带疟疾病原体恶性疟原虫中氧化还原稳态的重要管家酶。谷胱甘肽还原酶抑制剂本身被证明具有抗癌和抗疟活性，并有助于逆转耐药性。甲萘醌化学的发展导致选择 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] 己酸，称为 M(5)，作为两者的有效可逆和非竞争性抑制剂人和恶性疟原虫谷胱甘肽还原酶。在这里，我们描述了作为两种酶的基于机制的抑制剂的氟甲基-M(5) 类似物的合成和动力学表征。在酶催化过程中，硅化物底物被一电子或二电子还原激活，然后在消除氟时产生高反应性的醌甲基化物。因此，发现人类酶不可逆地失活，ak(inact) 值为 0.4 +/- 0.2 min(-1)。烷基化酶的晶体结构以 1.7 A 分辨率解析。它表明抑制剂与活性位点 Cys58 共价结合，并与 His467'、Arg347、Arg37 和 Tyr114 非共价相互作用。基于

  DOI：

  10.1021/ja061155v

文献信息

• [EN] 1,4-NAPHTHOQUINONE DERIVATIVES AND THERAPEUTIC USE THEREOF<br/>[FR] DÉRIVÉS DE 1,4-NAPHTOQUINONE ET UTILISATION THÉRAPEUTIQUE DE CEUX-CI
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2009118327A1

  公开（公告）日：2009-10-01

  Derivatives of formula (I) wherein A is selected from the following rings: and their preparation and their application as antimalarial agents.

  公式(I)的衍生物，其中A从以下环中选择：它们的制备及其作为抗疟疾药物的应用。
• 1,4-NAPHTHOQUINONE DERIVATIVES AND THERAPEUTIC USE THEREOF
  申请人：Centre National de la Recherche Scientifique

  公开号：EP2257515B1

  公开（公告）日：2017-05-17
• US9090549B2
  申请人：——

  公开号：US9090549B2

  公开（公告）日：2015-07-28
• A Fluoro Analogue of the Menadione Derivative 6-[2‘-(3‘-Methyl)-1‘,4‘-naphthoquinolyl]hexanoic Acid Is a Suicide Substrate of Glutathione Reductase. Crystal Structure of the Alkylated Human Enzyme
  作者：Holger Bauer、Karin Fritz-Wolf、Andreas Winzer、Sebastian Kühner、Susan Little、Vanessa Yardley、Hervé Vezin、Bruce Palfey、R. Heiner Schirmer、Elisabeth Davioud-Charvet

  DOI：10.1021/ja061155v

  日期：2006.8.1

  cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive

  谷胱甘肽还原酶是人体细胞和热带疟疾病原体恶性疟原虫中氧化还原稳态的重要管家酶。谷胱甘肽还原酶抑制剂本身被证明具有抗癌和抗疟活性，并有助于逆转耐药性。甲萘醌化学的发展导致选择 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] 己酸，称为 M(5)，作为两者的有效可逆和非竞争性抑制剂人和恶性疟原虫谷胱甘肽还原酶。在这里，我们描述了作为两种酶的基于机制的抑制剂的氟甲基-M(5) 类似物的合成和动力学表征。在酶催化过程中，硅化物底物被一电子或二电子还原激活，然后在消除氟时产生高反应性的醌甲基化物。因此，发现人类酶不可逆地失活，ak(inact) 值为 0.4 +/- 0.2 min(-1)。烷基化酶的晶体结构以 1.7 A 分辨率解析。它表明抑制剂与活性位点 Cys58 共价结合，并与 His467'、Arg347、Arg37 和 Tyr114 非共价相互作用。基于
• Antimalarial Dual Drugs Based on Potent Inhibitors of Glutathione Reductase from <i>Plasmodium falciparum</i>
  作者：Wolfgang Friebolin、Beate Jannack、Nicole Wenzel、Julien Furrer、Thomas Oeser、Cecilia P. Sanchez、Michael Lanzer、Vanessa Yardley、Katja Becker、Elisabeth Davioud-Charvet

  DOI：10.1021/jm7009292

  日期：2008.3.13

  Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe-III)protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.