PDF(Pubmed)
Abstract：
In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.
摘要：
在这项工作中,我们已经报告了设计，合成，在体外，以及新型双-4-羟基香豆素基苯氧基-1,2,3-三唑-N-苯乙酰胺衍生物5a-m作为有效的α-葡萄糖苷酶抑制剂的硅酶评估。与阳性对照阿卡波糖（IC50=750.0±0.6µM）相比，所有合成的类似物均显示出对α-葡萄糖苷酶的高抑制作用（IC50值在6.0±0.2至85.4±2.3µM之间）。在新合成的化合物5a-m中，2,4-二氯-N-苯乙酰胺衍生物5i的抑制作用比阿卡波糖高约125倍被确定为最有效的条目。对标题化合物5a-m的构效关系（SAR）研究表明，这些化合物的抑制作用取决于N-苯基乙酰胺环上的取代模式。通过分子对接研究评估了重要类似物（根据SAR研究）的酶活性位点的相互作用模式和结合能。还评估了最有效的化合物5i的分子动力学和药代动力学性质和毒性的预测,并将获得的数据与阿卡波糖进行比较。
