Design, synthesis, molecular docking, and ADME prediction evaluation of phenyloxazole derivatives as α-glucosidase inhibitors

Abstract

A class of new phenyloxazole derivatives (6a-6p) was synthesized, and their inhibitory activities towards α-glucosidase were researched. All synthesized compounds displayed potential inhibition activity towards α-glucosidase with IC50 values ranging between 48.78 ± 4.31 μM to 127.45 ± 1.86 μM. Thereinto, compound 6n displayed the best activity with IC50 of 48.78 ± 4.31 μM in comparison with the standard acarbose (IC50 = 576.27 ± 13.33 μM). Enzyme kinetic result indicated that 6n is a mixed-type inhibitor towards α-glucosidase (Ki = 10.62 μM). Furthermore, the action mechanism between 6n and α-glucosidase was obtained by using the fluorescence spectrometer, circular dichroism, and molecular docking. Fluorescence quenching indicates that the quenching mode of compound 6n against the α-glucosidase was static quenching, Ka and the number of binding sites n was determined as 2.75 × 105M−1 and 1, respectively. The circular dichroism results suggested that it can change the secondary structure of α-glucosidase and reduce its activity. Molecular docking revealed that 6n and α-glucosidase formed CH-π interaction by binding with Phe-157 and Phe-117. In vitro, cytotoxicity studies demonstrated 6n has low cytotoxicity. Moreover, ADME prediction indicated that most compounds are likely to be orally active.