Benzonate derivatives of acetophenone as potent α-glucosidase inhibitors: synthesis structure–activity relationship and mechanism

摘要

In this article, 23 compounds (>6 and >7a–>7v) were prepared and evaluated for their in vitro α-glucosidase inhibitory activity. The compounds >7d, >7f, >7i, >7n, >7o, >7r, >7s, >7u, and >7v displayed the α-glucosidase inhibition activity with IC50 values ranging from 1.68 to 7.88 µM. Among all tested compounds, >7u was found to be the most efficient, being 32-fold more active than the standard drug acarbose, which significantly attenuated postprandial blood glucose in mice. In addition, the compound >7u also induced the fluorescence quenching and conformational changes of enzyme, by forming α-glucosidase–>7u complex in a mixed inhibition type. The thermodynamic constants recognised the interaction between >7u and α-glucosidase and was an enthalpy-driven spontaneous exothermic reaction. The synchronous fluorescence and CD spectra also indicate that the compound >7u changed the enzyme conformation. The findings identify the binding interactions between new ligands and α-glucosidase and reveal the compound >7u as a potent α-glucosidase inhibitor.