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Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-11-29 , DOI: 10.1016/j.bioorg.2018.11.038
Mahnaz Yazdani 1 , Najmeh Edraki 2 , Rashid Badri 3 , Mehdi Khoshneviszadeh 2 , Aida Iraji 2 , Omidreza Firuzi 2
Affiliation  

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO2 groups at the para position of the phenyl ring, namely compounds 7c (IC50 = 8.55 ± 3.37 µM) and 7d (IC50 = 11.42 ± 2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC50 = 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.

中文翻译:

含苯氧基甲基-1,2,3-三唑侧链的3-肼基1,2,4-三嗪支架衍生的抗阿尔茨海默氏病的多靶点抑制剂:设计,合成和生物学评估。

阿尔茨海默氏病(AD)是一种复杂的神经系统疾病,具有多种潜在的病理过程。几条证据表明,BACE1是AD发病机理中的关键酶,其抑制作用在AD治疗中尤为重要。合成了十个带有芳基苯氧基甲基-1,2,3-三唑侧基的新的3-肼基-1,2,4-三嗪作为抗AD的多功能配体。我们表明,在苯环对位含有Cl和NO2基团的化合物,即化合物7c(IC50 = 8.55±3.37 µM)和7d(IC50 = 11.42±2.01 µM),具有有希望的BACE1抑制潜力。此外,我们评估了PC12神经元细胞系中7c和7d衍生物的神经保护活性,它们对淀粉样β肽毒性显示出中度保护作用。此外,化合物7d表现出金属螯合活性和适度的抗氧化电位(IC50 = 44.42±7.33 µM)。这些分子的分子对接研究表明与BACE1的多个氨基酸具有高亲和力结合,这对于有效抑制至关重要。这些结果表明,带有芳基苯氧基甲基-1,2,3-三唑的1,2,4-三嗪衍生物具有作为AD治疗剂的有希望的性能。
更新日期:2018-11-29
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