N,N'-bis(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)butane-1,4-diamine | 326801-38-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N,N'-bis(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)butane-1,4-diamine
• CAS: 326801-38-1
• 化学式: C₃₀H₃₂Cl₂N₄
• 分子量: 519.517
• InChiKey: MWLFWFDAMMIREO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  49.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氨基-4-氯苯甲酸 在 sodium iodide 、 三氯氧磷 作用下， 以 苯酚 为溶剂， 反应 1.0h， 生成 N¹-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)butane-1,4-diamine 、 N,N'-bis(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)butane-1,4-diamine
  参考文献：
  名称：

  Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes

  摘要：

  利什曼病是现代最被忽视的疾病之一，主要影响热带、亚热带和地中海盆地的发展中国家人群，约有3.5亿人可能患上该病。由于预防和治疗措施的失败，人类利什曼病的发病率在过去几十年中增加了，目前没有疫苗和化疗，这是一个问题。吖啶衍生物是一类氮杂环化合物，与众多生物活性相关，尤其是它们的抗利什曼病潜力。本研究基于对寄生虫酶S-腺苷甲硫氨酸脱羧酶（AdoMet DC）的计算研究，发现多种1,2,3,4-四氢-吖啶可能是潜在的抑制剂，表明该支架是新型抗利什曼病药物的有前途的构建块。因此，合成了多种1,2,3,4-四氢吖啶衍生物，评估了它们对利什曼原虫（利什曼原虫）幼虫的活性，并根据所得结果开展了结构-活性关系（SAR）研究。尽管大多数评估的1,2,3,4-四氢吖啶衍生物表现出高毒性，但本研究收集的结构信息使其可以与另一个支架（喹啉）结合使用，导致获得N1，N12-双（7-氯喹啉-4-基）十二烷基-1,12-二胺（12）作为有前途的新型抗利什曼病药物（IC50 = 0.60±0.11μM，EC50 = 11.69±3.96μM和TI = 19.48）。

  DOI：

  10.3390/pharmaceutics15020669

文献信息

• Pyrano[3,2-<i>c</i>]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds
  作者：Pelayo Camps、Xavier Formosa、Carles Galdeano、Diego Muñoz-Torrero、Lorena Ramírez、Elena Gómez、Nicolás Isambert、Rodolfo Lavilla、Albert Badia、M. Victòria Clos、Manuela Bartolini、Francesca Mancini、Vincenza Andrisano、Mariana P. Arce、M. Isabel Rodríguez-Franco、Óscar Huertas、Thomai Dafni、F. Javier Luque

  DOI：10.1021/jm900859q

  日期：2009.9.10

  Two isomeric series of dual binding site acetyleholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (A beta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]-quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced A beta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.
• Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes
  作者：Carlos F. M. Silva、Teresa Leão、Filipa Dias、Ana M. Tomás、Diana C. G. A. Pinto、Eduardo F. T. Oliveira、Ana Oliveira、Pedro A. Fernandes、Artur M. S. Silva

  DOI：10.3390/pharmaceutics15020669

  日期：——

  Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

  利什曼病是现代最被忽视的疾病之一，主要影响热带、亚热带和地中海盆地的发展中国家人群，约有3.5亿人可能患上该病。由于预防和治疗措施的失败，人类利什曼病的发病率在过去几十年中增加了，目前没有疫苗和化疗，这是一个问题。吖啶衍生物是一类氮杂环化合物，与众多生物活性相关，尤其是它们的抗利什曼病潜力。本研究基于对寄生虫酶S-腺苷甲硫氨酸脱羧酶（AdoMet DC）的计算研究，发现多种1,2,3,4-四氢-吖啶可能是潜在的抑制剂，表明该支架是新型抗利什曼病药物的有前途的构建块。因此，合成了多种1,2,3,4-四氢吖啶衍生物，评估了它们对利什曼原虫（利什曼原虫）幼虫的活性，并根据所得结果开展了结构-活性关系（SAR）研究。尽管大多数评估的1,2,3,4-四氢吖啶衍生物表现出高毒性，但本研究收集的结构信息使其可以与另一个支架（喹啉）结合使用，导致获得N1，N12-双（7-氯喹啉-4-基）十二烷基-1,12-二胺（12）作为有前途的新型抗利什曼病药物（IC50 = 0.60±0.11μM，EC50 = 11.69±3.96μM和TI = 19.48）。