8-(4-bromophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one | 227007-70-7

• 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: 8-(4-bromophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one
• 英文别名: 8-(4-Bromophenyl)-8-hydroxy-5-methyl-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one
• CAS: 227007-70-7
• 化学式: C₁₂H₉BrN₂O₃S
• 分子量: 341.185
• InChiKey: BQAKEYSLSCKIOQ-UHFFFAOYSA-N

物化性质

• 沸点：
  451.8±55.0 °C(Predicted)
• 密度：
  1.81±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  87.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-(4-bromophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one 在 对甲苯磺酸 、 三乙胺 作用下， 以 甲苯 为溶剂， 反应 5.0h， 生成 8-(4-bromophenyl)-5-methyl-8-(2-piperidin-1-ylethoxy)-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one
  参考文献：
  名称：

  Playing with Opening and Closing of Heterocycles: Using the Cusmano-Ruccia Reaction to Develop a Novel Class of Oxadiazolothiazinones, Active as Calcium Channel Modulators and P-Glycoprotein Inhibitors

  摘要：

  由于硝基咪唑衍生物的环到环转变，我们获得了一个分子骨架，适当修饰后能够通过阻断L型钙通道来降低心肌收缩力。先前，我们利用这个骨架开发了一个定量构效关系（QSAR）模型，并使用其中效力最强的二唑硫嗪酮作为基于配体的虚拟筛选模板。在此，我们扩展了化学修饰的多样性，提供了11种新衍生物的合成和体外数据，并且利用最新的计算机技术开发了一个新的三维QSAR模型。我们观察到了二唑酮部分的关键作用：鉴于跨膜通道蛋白中存在带正电的钙离子，我们假设二唑硫嗪酮、钙离子和蛋白质之间形成了三元复合物。通过生成药效团并将其对接进蛋白质的同源模型中，我们支持了这一假设。我们还利用对接实验研究了与P-糖蛋白同源模型的相互作用，这一系列的分子能够抑制P-糖蛋白，并为这个骨架在生物相互作用中的相关性提供了更多证据。

  DOI：

  10.3390/molecules191016543
• 作为产物：
  描述：

  6-(4-Bromophenyl)-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazole 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 2.5h， 以24%的产率得到8-(4-bromophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one
  参考文献：
  名称：

  Ring-ring interconversions. Part 2. Effect of the substituent on the rearrangement of 6-aryl-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazoles into 8-aryl-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones. A novel class of potential antitumor agents

  摘要：

  The reaction of several 6-aryl-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazoles with hydrochloric acid by refluxing in ethanol gives new 8-aryl-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c] [1,2,4]oxadiazol-3-ones for testing of their biological activity. By carrying out the reaction at room temperature it has been possible to isolate reaction intermediates to which structures have been assigned. This study has provided information on the reaction mechanism and on the effect of the substituent in the phenyl ring on the yield of the reaction. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(99)00189-1

文献信息

• A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives
  作者：Roberta Budriesi、Emanuele Carosati、Alberto Chiarini、Barbara Cosimelli、Gabriele Cruciani、Pierfranco Ioan、Domenico Spinelli、Raffaella Spisani

  DOI：10.1021/jm0493414

  日期：2005.4.1

  In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c] [1,2,4]-oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC50 = 0.04 mu M), which is 20 times more active than diltiazern (EC50 = 0.79 mu M), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.
• Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones
  作者：Emanuele Carosati、Pierfranco Ioan、Giovanni Battista Barrano、Salvatore Caccamese、Barbara Cosimelli、Frank J. Devlin、Elda Severi、Domenico Spinelli、Stefano Superchi、Roberta Budriesi

  DOI：10.1016/j.ejmech.2014.12.044

  日期：2015.3

  Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 mu M) and 3b (EC50 = 0.006 mu M). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)I(R)-(-). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 mu M) and 259-fold more potent than the S-one. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Inhibition of MDR1 Activity in Vitro by a Novel Class of Diltiazem Analogues: Toward New Candidates
  作者：Maurizio Viale、Cinzia Cordazzo、Barbara Cosimelli、Daniela de Totero、Patrizio Castagnola、Cinzia Aiello、Elda Severi、Giovanni Petrillo、Maurizio Cianfriglia、Domenico Spinelli

  DOI：10.1021/jm801195k

  日期：2009.1.22

  The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c]-[1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC50 reduction >= 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its anti proliferative activity in multidrug resistant A2780/DX3 cells.
• ABCB1 Structural Models, Molecular Docking, and Synthesis of New Oxadiazolothiazin-3-one Inhibitors
  作者：Camillo Rosano、Maurizio Viale、Barbara Cosimelli、Elda Severi、Rosaria Gangemi、Alessia Ciogli、Daniela De Totero、Domenico Spinelli

  DOI：10.1021/ml300436x

  日期：2013.8.8

  Docking methods are powerful tools for in silico screening and drug lead generation and optimization. Here, we describe the synthesis of new inhibitors of ABCB1 whose design was based on construction and preliminary confirmation of a model for this membrane transporter of the ATP-binding cassette family. We chose the strategy to build our three-dimensional model of the ABCB1 transporter by homology. Atomic coordinates were then assayed for their reliability using the measured activity of some oxadiazolothiazin-3-one compounds. Once established their performance by docking analysis, we synthesized new compounds whose forecasted activity was tested by MTT and cytofluorimetric assays. Our docking model of MDR1, MONBD1, seems to reliably satisfy our need to design and forecast, on the basis of their LTCC blockers ability, the inhibitory activity of new molecules on the ABCB1 transporter.
• Playing with Opening and Closing of Heterocycles: Using the Cusmano-Ruccia Reaction to Develop a Novel Class of Oxadiazolothiazinones, Active as Calcium Channel Modulators and P-Glycoprotein Inhibitors
  作者：Domenico Spinelli、Roberta Budriesi、Barbara Cosimelli、Elda Severi、Matteo Micucci、Massimo Baroni、Fabio Fusi、Pierfranco Ioan、Simon Cross、Maria Frosini、Simona Saponara、Rosanna Matucci、Camillo Rosano、Maurizio Viale、Alberto Chiarini、Emanuele Carosati

  DOI：10.3390/molecules191016543

  日期：——

  As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions.

  由于硝基咪唑衍生物的环到环转变，我们获得了一个分子骨架，适当修饰后能够通过阻断L型钙通道来降低心肌收缩力。先前，我们利用这个骨架开发了一个定量构效关系（QSAR）模型，并使用其中效力最强的二唑硫嗪酮作为基于配体的虚拟筛选模板。在此，我们扩展了化学修饰的多样性，提供了11种新衍生物的合成和体外数据，并且利用最新的计算机技术开发了一个新的三维QSAR模型。我们观察到了二唑酮部分的关键作用：鉴于跨膜通道蛋白中存在带正电的钙离子，我们假设二唑硫嗪酮、钙离子和蛋白质之间形成了三元复合物。通过生成药效团并将其对接进蛋白质的同源模型中，我们支持了这一假设。我们还利用对接实验研究了与P-糖蛋白同源模型的相互作用，这一系列的分子能够抑制P-糖蛋白，并为这个骨架在生物相互作用中的相关性提供了更多证据。