N-(4-((diethylamino)methyl)-3-hydroxyphenyl)acetamide | 459133-35-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(4-((diethylamino)methyl)-3-hydroxyphenyl)acetamide
• 英文别名: N-[4-[(Diethylamino)methyl]-3-hydroxyphenyl]acetamide；N-[4-(diethylaminomethyl)-3-hydroxyphenyl]acetamide
• CAS: 459133-35-8
• 化学式: C₁₃H₂₀N₂O₂
• 分子量: 236.314
• InChiKey: USKVVSHKVGPAHH-UHFFFAOYSA-N

物化性质

• 沸点：
  405.0±40.0 °C(Predicted)
• 密度：
  1.122±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  52.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(4-((diethylamino)methyl)-3-hydroxyphenyl)acetamide 在 盐酸 作用下， 生成 5-[(7-氯-4-喹啉基)氨基]-2-[(二乙基氨基)甲基]苯酚
  参考文献：
  名称：

  氨基烷基酚作为抗疟药（杂环氨基）-α-氨基-邻甲酚；迷彩的合成。

  摘要：

  DOI：

  10.1021/ja01184a023
• 作为产物：
  描述：

  3-氨基苯酚 以 四氢呋喃 、 乙醇 为溶剂， 反应 1.5h， 生成 N-(4-((diethylamino)methyl)-3-hydroxyphenyl)acetamide
  参考文献：
  名称：

  具有曼尼希碱基侧链的抗疟原虫吡啶并[1,2-a]苯并咪唑衍生物：合成，药理学评估和活性代谢物捕集研究。

  摘要：

  合成了一系列新型的带有曼尼希碱基侧链的吡啶并[1,2-a]苯并咪唑及其代谢物，并对其在小鼠中的体外抗疟原虫活性，微粒体代谢稳定性，反应性代谢产物（RM）形成和体内抗疟疾功效进行了评估。模型。在伯氏疟原虫感染的小鼠中口服4×50 mg / kg的一种衍生物可将寄生虫病降低95％，平均存活期为治疗后16天。这些衍生物的体内功效可能是其活性代谢产物的结果，其中两种代谢产物显示出对氯喹敏感和多药耐药性恶性疟原虫（P. falciparum）菌株有效的体外抗疟原虫活性。观察到所有< 在肝微粒体中孵育30分钟后，剩余40％的母体化合物。RM捕集研究仅在带有4-氨基苯酚部分的衍生物中检测到了谷胱甘肽加合物，其片段签名表明该缀合发生在曼尼希碱基侧链的苯环上。与氨二喹（AQ）一样，交换4-羟基和曼尼希碱基侧基的位置或用氟取代4-羟基似乎阻止了AQ-like衍生物的生物活化，尽管这是以抗疟原虫活性为代价的，这大大降低了抗疟原虫的活性。

  DOI：

  10.1021/acsinfecdis.8b00279

文献信息

• Incorporation of Basic Side Chains into Cryptolepine Scaffold: Structure−Antimalarial Activity Relationships and Mechanistic Studies
  作者：João Lavrado、Ghislain G. Cabal、Miguel Prudêncio、Maria M. Mota、Jiri Gut、Philip J. Rosenthal、Cecília Díaz、Rita C. Guedes、Daniel J. V. A. dos Santos、Elena Bichenkova、Kenneth T. Douglas、Rui Moreira、Alexandra Paulo

  DOI：10.1021/jm101383f

  日期：2011.2.10

  The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies

  报道了在C-11位上含有基本侧链的隐肾上腺素衍生物的合成及其抗血浆和细胞毒性的评价。丙基，丁基和环烷基二胺侧链显着提高了对耐氯喹的恶性疟原虫的活性与母体化合物相比，可降低细胞毒性。通过荧光显微镜对寄生虫血液阶段进行的定位研究表明，这些衍生物在核内积累，表明掺入碱性侧链不足以促进寄生虫在酸性消化液中的选择性积累。该系列中的大多数化合物都具有与双链DNA双链体以及单体血红素结合的能力，表明这些是与观察到的抗疟活性相关的可能靶标。总体而言，这些具有显着改善的抗疟原虫活性和选择性指数的新型隐氯仿类似物为开发抗药性疟疾寄生虫的有效且高度选择性的药物提供了有希望的起点。
• Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure–Activity Relationship and <i>In Vivo</i> Oral Efficacy Studies
  作者：Godwin Akpeko Dziwornu、Dina Coertzen、Meta Leshabane、Constance M. Korkor、Cleavon K. Cloete、Mathew Njoroge、Liezl Gibhard、Nina Lawrence、Janette Reader、Mariëtte van der Watt、Sergio Wittlin、Lyn-Marie Birkholtz、Kelly Chibale

  DOI：10.1021/acs.jmedchem.1c00354

  日期：2021.4.22

  A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure–activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues

  提出了一系列新的抗疟疾苯并咪唑衍生物，该衍生物在C2位上结合了酚类曼尼希碱侧链，具有无性血液和有性的双重活动。结构与活性之间的关系研究表明，与1 H-苯并咪唑类似物相比，1-苄基苯并咪唑类似物具有亚微摩尔无性血液和性阶段活动，而1 H-苯并咪唑类似物仅对无性血液阶段（ABS）寄生虫具有活性。此外，前者在ABS寄生虫中表现出微管抑制活性，但在II / III期配子细胞中表现出更显着的抑制作用。1 H-苯并咪唑类似物除了是血红蛋白形成的真正抑制剂外，还显示出对微管的抑制作用。体内对伯氏疟原虫感染的小鼠进行的功效研究表明，当以4×50 mg / kg口服给药时，领先的化合物41表现出很高的功效（寄生虫血症减少98％）。通常，该化合物对哺乳动物细胞无细胞毒性。
• [EN] ANTI-MALARIAL COMPOUNDS<br/>[FR] COMPOSES ANTI-MALARIA
  申请人：UNIV LIVERPOOL

  公开号：WO2002072554A1

  公开（公告）日：2002-09-19

  The present invention relates to pharmaceutical compounds for use in the treatment or porphylaxis of malaria having the general formula: where: R is selected from the group consisting of dimethylamino, diethylamino, di-N-propylamino, diisopropylamino, di-N-butylamino, di-sec-butylamino, piperidinyl, piperizinyl, ethylamino, tert-butylamino; and X is selected from the group consisting of chloro, fluoro, iodo, bromo, trifluoromethyl, methoxy and methyl.

  本发明涉及一种用于治疗或预防疟疾的药物化合物，其通式为：其中：R选自二甲氨基，二乙氨基，二-N-丙基氨基，二异丙基氨基，二-N-丁基氨基，二-sec-丁基氨基，哌啶基，哌嗪基，乙基氨基，叔丁基氨基等组成的群体；X选自氯，氟，碘，溴，三氟甲基，甲氧基和甲基等组成的群体。
• Anti-malarial compounds
  申请人：——

  公开号：US20040152729A1

  公开（公告）日：2004-08-05

  The present invention relates to pharmaceutical compounds for use in the treatment or porphylaxis of malaria having the general formula: where: R is selected from the group consisting of dimethylamino, diethylamino, di-N-propylamino, diisopropylamino, di-N-butylamino, di-sec-butylamino, piperidinyl, piperizinyl, ethylamino, tert-butylamino; and X is selected from the group consisting of chloro, fluoro, iodo, bromo, trifluoromethyl, methoxy and methyl. 1

  本发明涉及用于治疗或预防疟疾的药物化合物，其一般公式为：其中：R选自二甲氨基，二乙氨基，二-N-丙基氨基，二异丙基氨基，二-N-丁基氨基，二-sec-丁基氨基，哌啶基，哌嗪基，乙基氨基，叔丁基氨基等组成的群体；X选自氯，氟，碘，溴，三氟甲基，甲氧基和甲基等组成的群体。
• Isoquine and Related Amodiaquine Analogues:  A New Generation of Improved 4-Aminoquinoline Antimalarials
  作者：Paul M. O'Neill、Amira Mukhtar、Paul A. Stocks、Laura E. Randle、Stephen Hindley、Stephen A. Ward、Richard C. Storr、Jamie F. Bickley、Ian A. O'Neil、James L. Maggs、Ruth H. Hughes、Peter A. Winstanley、Patrick G. Bray、B. Kevin Park

  DOI：10.1021/jm030796n

  日期：2003.11.1

  Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.