(+)-(S)-1-(6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(4-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea

• 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: (+)-(S)-1-(6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(4-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea
• 英文别名: 1-[(10~{b}~{S})-6-oxidanylidene-2,3,4,10~{b}-tetrahydro-1~{H}-pyrido[2,1-a]isoindol-10-yl]-3-[4-[1-[2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]-1,2,3-triazol-4-yl]pyridin-2-yl]urea；1-[(10bS)-6-oxo-2,3,4,10b-tetrahydro-1H-pyrido[2,1-a]isoindol-10-yl]-3-[4-[1-[2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]triazol-4-yl]pyridin-2-yl]urea
• 化学式: C₃₅H₃₅N₉O₂
• 分子量: 613.722
• InChiKey: BNBWNJAILLASJW-PMERELPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  46
• 可旋转键数：
  7
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(羟甲基)吡啶-2-羧酸 在 盐酸 、 氯化亚砜 、 copper(ll) sulfate pentahydrate 、 (+)-sodium ascorbate 、 (1-重氮基-2-氧代丙基)膦酸二甲酯 、 potassium carbonate 、 一水合肼 、 乙酸乙酯 、 sodium nitrite 、 2-碘酰基苯甲酸 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.75h， 生成 (+)-(S)-1-(6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(4-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea
  参考文献：
  名称：

  Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

  摘要：

  Both cholinesterases (AChE and BChE) and kinases, such as GSK-3 alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3 alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3 alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.12.063

文献信息

• Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3
  作者：Killian Oukoloff、Nicolas Coquelle、Manuela Bartolini、Marina Naldi、Rémy Le Guevel、Stéphane Bach、Béatrice Josselin、Sandrine Ruchaud、Marco Catto、Leonardo Pisani、Nunzio Denora、Rosa Maria Iacobazzi、Israel Silman、Joel L. Sussman、Frédéric Buron、Jacques-Philippe Colletier、Ludovic Jean、Sylvain Routier、Pierre-Yves Renard

  DOI：10.1016/j.ejmech.2018.12.063

  日期：2019.4

  Both cholinesterases (AChE and BChE) and kinases, such as GSK-3 alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3 alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3 alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp. (C) 2019 Elsevier Masson SAS. All rights reserved.