Design, synthesis and biological evaluation of novel oxazole derivatives as potential hypoglycemic agents

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-18 DOI:10.1016/j.bmc.2024.117961

Ruifeng Wang , Ke Chen , Shuihua Liu , Ruyue Ren , Hongbao Hou , Qingxuan Zeng , Yi Zhang , Yunfeng Liu

引用次数: 0

Abstract

A series of 2,4-disubstituted-oxazole derivatives have been designed and synthesized based on compound 3a, a promising lead compound developed in our lab. Among these derivatives, the optimized compound 5k exhibited potent hypoglycemic activity, increasing glucose consumption by 60 % in HepG2 cells compared to the solvent control, and its activity was higher than that of metformin. Further investigation indicated that compound 5k exhibited negligible cytotoxic effects at a concentration of 25 μM in HepG2 and 3T3-L1 cells and showed moderate inhibitory activity against various subtypes of human cytochrome P450 subtypes. An oral glucose tolerance test confirmed that 5k is an effective hypoglycemic agent. Additionally, mechanistic studies suggested that 5k may exert its hypoglycemic activity through the activation of the AMPK pathway.

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作为潜在降糖药的新型噁唑衍生物的设计、合成和生物学评价。

以我们实验室开发的前景看好的先导化合物 3a 为基础，设计并合成了一系列 2,4-二取代噁唑衍生物。在这些衍生物中，优化后的化合物 5k 表现出了强效的降血糖活性，与溶剂对照相比，它能使 HepG2 细胞的葡萄糖消耗量增加 60%，其活性高于二甲双胍。进一步的研究表明，当浓度为 25 μM 时，化合物 5k 在 HepG2 和 3T3-L1 细胞中的细胞毒性作用可忽略不计，并且对人类细胞色素 P450 的各种亚型具有中等程度的抑制活性。口服葡萄糖耐量试验证实 5k 是一种有效的降血糖药。此外，机理研究表明，5k 可能通过激活 AMPK 途径发挥降血糖活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.