7-(4-bromobutoxy)-3,4-dimethyl-2H-chromen-2-one | 1440946-54-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 7-(4-bromobutoxy)-3,4-dimethyl-2H-chromen-2-one
• 英文别名: 7-(4-bromobutyloxy)-3,4-dimethylcoumarin
• CAS: 1440946-54-2
• 化学式: C₁₅H₁₇BrO₃
• 分子量: 325.202
• InChiKey: OKYBZSZQRGJNES-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.96
• 重原子数：
  19.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  39.44
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  7-(4-bromobutoxy)-3,4-dimethyl-2H-chromen-2-one 、 6-氟-3-(哌啶-4-基)苯并[D]异恶唑 在 potassium carbonate 、 potassium iodide 作用下， 以 乙腈 为溶剂， 以80.9%的产率得到7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-3,4-dimethyl-2H-chromen-2-one
  参考文献：
  名称：

  Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics

  摘要：

  The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine 132, D3, and serotonin S-HT1A and S-HT2A, receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H- chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D-2 and D-3 and serotonin S-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for S-HT2C and H-1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

  DOI：

  10.1021/jm400408r
• 作为产物：
  描述：

  2-甲基乙酰乙酸乙酯 在 硫酸 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 7-(4-bromobutoxy)-3,4-dimethyl-2H-chromen-2-one
  参考文献：
  名称：

  Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics

  摘要：

  The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine 132, D3, and serotonin S-HT1A and S-HT2A, receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H- chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D-2 and D-3 and serotonin S-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for S-HT2C and H-1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

  DOI：

  10.1021/jm400408r

文献信息

• Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents
  作者：Leonardo Pisani、Roberta Farina、Marco Catto、Rosa Maria Iacobazzi、Orazio Nicolotti、Saverio Cellamare、Giuseppe Felice Mangiatordi、Nunzio Denora、Ramon Soto-Otero、Lydia Siragusa、Cosimo Damiano Altomare、Angelo Carotti

  DOI：10.1021/acs.jmedchem.6b00562

  日期：2016.7.28

  targets for Alzheimer’s disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies

  为了调节阿尔茨海默氏病（AD）的两个关键酶标，即乙酰胆碱酯酶（AChE）和单胺氧化酶B（MAO B），通过将3,4-二甲基香豆素骨架与1,3连接起来，适当设计了一系列多目标配体-和1，4-取代的哌啶部分，从而调节碱性以改善亲水/亲脂平衡。经过体外酶抑制试验后，在基于人SH-SY5Y细胞的模型中确定并评估了分别对hMAO B和eeAChE表现出纳摩尔浓度和低微摩尔浓度效价的多能抑制剂，以其对氧化毒素的细胞毒性和神经保护作用（H 2 O 2，鱼藤酮和oligomycin-A）。本研究导致鉴定出具有高hMAO B抑制活性（IC 50 = 30 nM）和良好的MAO B / A选择性（选择性指数，SI = 94）以及微摩尔eeAChE抑制作用的有前途的多目标命中化合物（5b）（IC 50 = 1.03μM）。此外，5b表现为一种水溶性的，可透脑的神经保护剂，可抵抗氧化损伤，而不会与P-gp外排系统相互作用。
• Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation
  作者：Qi He、Jing Liu、Jin-Shuai Lan、Jiaoli Ding、Yongbing Sun、Yuanying Fang、Neng Jiang、Zunhua Yang、Liyuan Sun、Yi Jin、Sai-Sai Xie

  DOI：10.1016/j.bioorg.2018.09.010

  日期：2018.12

  A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 mu M and 0.0089 mu M for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 mu M for hAChE; 0.101 mu M for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
• 1,2,3,4-Tetrahydroisoquinoline/2H-chromen-2-one conjugates as nanomolar P-glycoprotein inhibitors: Molecular determinants for affinity and selectivity over multidrug resistance associated protein 1
  作者：Mariagrazia Rullo、Mauro Niso、Leonardo Pisani、Antonio Carrieri、Nicola Antonio Colabufo、Saverio Cellamare、Cosimo Damiano Altomare

  DOI：10.1016/j.ejmech.2018.10.043

  日期：2019.1

  A series of conjugates bearing a 1,2,3,4-tetrahydroisoquinoline motif linked to substituted 7-hydroxy-2H-chromen-2-ones was synthesized and assayed through calcein-AM test in Madin-Darby Canine Kidney (MDCK) cells overexpressing P-glycoprotein (P-gp) and closely related multidrug resistance associated protein 1 (MRP1) to probe the interference with efflux mechanisms mediated by P-gp and MRP1, respectively. A number of substituents at C3 and C4 of coumarin nucleus along with differently sized and shaped spacers was enrolled to investigate the effects of focused structural modifications over affinity and selectivity. Linker length and flexibility played a key role in enhancing P-gp affinity as proved by the most potent P-gp modulator (3h, IC50 = 70 nM). A phenyl ring within the spacer (3k, 3l, 3o) and bulkier groups (Br in 3r, Ph in 3u) at coumarin C3 led to derivatives showing nanomolar activity (160 nM < IC50 < 280 nM) along with outstanding selectivity over MRP1 (SI > 350). Molecular docking calculations carried out on a human MDR1 homology model structure contributed to gain insights into the ligands' binding modes. Some compounds (3d, 3h, 3l, 3r, 3t, 3u) reversed MDR thereby restoring doxorubicin cytotoxicity when co-administered with the drug into MDCK-MDR1 cells. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Structure-Based Design and Optimization of Multitarget-Directed 2<i>H</i>-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases
  作者：Roberta Farina、Leonardo Pisani、Marco Catto、Orazio Nicolotti、Domenico Gadaleta、Nunzio Denora、Ramon Soto-Otero、Estefania Mendez-Alvarez、Carolina S. Passos、Giovanni Muncipinto、Cosimo D. Altomare、Alessandra Nurisso、Pierre-Alain Carrupt、Angelo Carotti

  DOI：10.1021/acs.jmedchem.5b00599

  日期：2015.7.23

  The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta-and para-xylyl linkers, displayed: good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring art improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.