2-(4-chlorobenzyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde | 1620897-81-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(4-chlorobenzyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
• 英文别名: 6-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde；6-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
• CAS: 1620897-81-5
• 化学式: C₁₈H₁₁Cl₂N₃OS
• 分子量: 388.277
• InChiKey: XRTYWKLKORGNIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  75.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-吲哚酮 、 2-(4-chlorobenzyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 在 哌啶 作用下， 以 甲醇 为溶剂， 以83%的产率得到3-((2-(4-chlorobenzyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene)-1,3-dihydro-2H-indol-2-one
  参考文献：
  名称：

  Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain

  摘要：

  The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL‐xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well‐studied BH3 domain targeting.

  DOI：

  10.1111/febs.13815
• 作为产物：
  描述：

  2-氨基-5-(4-氯苄基)-1,3,4-噻二唑 在 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 8.0h， 生成 2-(4-chlorobenzyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
  参考文献：
  名称：

  Synthesis, Characterization and Anti-inflammatory Activity of 2-(4-chlorobenzyl)-5-(di(5- substituted-1H-indol-3-yl)methyl)-6-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazoles

  摘要：

  在本研究中，通过1H NMR、13C NMR光谱研究，评估了一系列2-(4-氯苄基)-5-(二(5-取代-1H-吲哚-3-基)甲基)-6-(4-取代苯基)咪唑并[2,1-b][1,3,4]噻二唑醇类化合物(5a-e)的抗炎潜力。合成化合物的初步毒性和抗炎效力通过对RAW264.7巨噬细胞系的评估来确定它们的IC50值。化合物5a-e进一步在瑞士白化大鼠中进行抗炎活性测试，使用1%卡拉胶诱导的爪水肿模型。化合物5a被选为主要化合物，并进一步考虑进行行为评估，如爬楼梯和运动能力练习。爪水肿在0、1、2、3、4和24小时的时间间隔内进行分析，爬楼梯和运动能力测试在接受试验化合物24小时后进行。本研究结果表明，化合物5a显著减少爪厚度68%，p < 0.001，并且与1%卡拉胶大鼠组相比，爬楼梯(增加1.5倍)和运动能力(增加1.6倍)提高。综上所述，本研究结果表明，化合物5a表现出强大的抗炎潜力，可作为进一步研究的临床前模板，作为当前非甾体类抗炎药的替代疗法。

  DOI：

  10.14233/ajchem.2020.22830

文献信息

• 2-(4-Chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles: Synthesis, cytotoxic activity and mechanism of action
  作者：Sujeet Kumar、Mahesh Hegde、Vidya Gopalakrishnan、Vinaya Kumar Renuka、Sureshbabu A. Ramareddy、Erik De Clercq、Dominique Schols、Anil Kumar Gudibabande Narasimhamurthy、Sathees C. Raghavan、Subhas S. Karki

  DOI：10.1016/j.ejmech.2014.07.054

  日期：2014.9

  The cytotoxic activity of a new series of 2-(4'-chlorobenzyl)-5,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle.
• Synthesis, Characterization and Anti-inflammatory Activity of 2-(4-chlorobenzyl)-5-(di(5- substituted-1H-indol-3-yl)methyl)-6-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazoles
  作者：Ayesha Siddiq、Sadashivamurthy Shamanth、Mohammed Salman、K.K. Dharmappa、Mantelingu Kempegowda、Shankar Jayarama

  DOI：10.14233/ajchem.2020.22830

  日期：——

  In present study, the anti-inflammatory potential of a series of 2-(4-chlorobenzyl)-5-(di(5-substituted- 1H-indol-3-yl)methyl)-6-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazoles (5a-e) were evuluated after characterizing through 1H NMR, 13C NMR spectral studies. Initial toxicity and anti-inflammatory efficacy of synthesized compounds is evaluated against RAW264.7 macrophages cell line to derive at their IC50 values. Compounds 5a-e are further tested for their anti-inflammatory activity in Swiss albino rats using the 1% carrageenan-induced paw edema model. Compound 5a is taken as the lead compound and is further considered for behavioural evaluations such as stair climbing and motility exercises. Paw edema is analyzed at time intervals of 0, 1, 2, 3, 4 and 24 h and stair climbing and motility tests are surveyed after 24 h of exposure to the test compound. The results of present study show that the compound 5a significantly reduces the paw thickness by 68% at p < 0.001 and increased the stair climbing (1.5 folds) and motility (1.6 folds) when compared to the 1% carrageenan rat group. Conclusively the results of present study show that compound 5a exhibits strong anti-inflammatory potential that can be used as a preclinical template for further investigations as an alternative therapy to the current NSAIDs.

  在本研究中，通过1H NMR、13C NMR光谱研究，评估了一系列2-(4-氯苄基)-5-(二(5-取代-1H-吲哚-3-基)甲基)-6-(4-取代苯基)咪唑并[2,1-b][1,3,4]噻二唑醇类化合物(5a-e)的抗炎潜力。合成化合物的初步毒性和抗炎效力通过对RAW264.7巨噬细胞系的评估来确定它们的IC50值。化合物5a-e进一步在瑞士白化大鼠中进行抗炎活性测试，使用1%卡拉胶诱导的爪水肿模型。化合物5a被选为主要化合物，并进一步考虑进行行为评估，如爬楼梯和运动能力练习。爪水肿在0、1、2、3、4和24小时的时间间隔内进行分析，爬楼梯和运动能力测试在接受试验化合物24小时后进行。本研究结果表明，化合物5a显著减少爪厚度68%，p < 0.001，并且与1%卡拉胶大鼠组相比，爬楼梯(增加1.5倍)和运动能力(增加1.6倍)提高。综上所述，本研究结果表明，化合物5a表现出强大的抗炎潜力，可作为进一步研究的临床前模板，作为当前非甾体类抗炎药的替代疗法。
• Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain
  作者：Divyaanka Iyer、Supriya V. Vartak、Archita Mishra、Gunaseelan Goldsmith、Sujeet Kumar、Mrinal Srivastava、Mahesh Hegde、Vidya Gopalakrishnan、Mark Glenn、Mahesh Velusamy、Bibha Choudhary、Nagesh Kalakonda、Subhas S. Karki、Avadhesha Surolia、Sathees C. Raghavan

  DOI：10.1111/febs.13815

  日期：2016.9

  The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL‐xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well‐studied BH3 domain targeting.