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合成、体外评价、分子对接和动力学研究嘧啶并三唑杂合体系作为新型α-葡萄糖苷酶抑制剂。

Synthesis, in-vitro evaluation, molecular docking, and kinetic studies of pyridazine-triazole hybrid system as novel α-glucosidase inhibitors.

机构信息

Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

出版信息

Bioorg Chem. 2021 Apr;109:104670. doi: 10.1016/j.bioorg.2021.104670. Epub 2021 Feb 1.

Abstract

In this study, we reported the discovery of pyridazine based 1,2,3-triazole derivatives as inhibitors of α-glucosidase. All target compounds exhibited significant inhibitory activities against yeast and rat α-glucosidase enzymes compared to positive control, acarbose. The most potent compound 6j, ethyl 3-(2-(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)ethyl)-5,6-diphenylpyridazine-4-carboxylate exhibited IC values of 58, and 73 µM. Docking studies indicated the responsibility of hydrophobic and hydrogen bonding interactions in the ligand-enzyme complex stability. The in-vitro safety against the normal cell line was observed by toxicity evaluation of the selected compounds.

摘要

在这项研究中,我们报道了发现基于哒嗪的 1,2,3-三唑衍生物作为α-葡萄糖苷酶的抑制剂。与阳性对照阿卡波糖相比,所有目标化合物对酵母和大鼠α-葡萄糖苷酶均显示出显著的抑制活性。最有效的化合物 6j,即乙基 3-(2-(1-(4-硝基苄基)-1H-1,2,3-三唑-4-基)乙基)-5,6-二苯基哒嗪-4-羧酸酯,其 IC 值分别为 58 和 73µM。对接研究表明,在配体-酶复合物稳定性中,疏水和氢键相互作用起重要作用。通过对选定化合物的毒性评估,观察到对正常细胞系的体外安全性。

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