Abstract
Nineteen biscoumarins were synthesized, well-characterized, and evaluated against α-glucosidases in vitro. Of these, six compounds (10, 12, 16, and 17-19) were newly synthesized and not previously reported in the chemical literature. The majority of the synthesized derivatives demonstrated significant inhibitory activity. A quantitative structure-activity relationship (QSAR) model was developed, revealing a strong correlation between the anti-α-glucosidase activity and selected molecular descriptors. Based on this model, two new compounds (18 and 19) were designed, which exhibited the strongest inhibition with IC50 values of 0.62 and 1.21 μM, respectively, when compared to the positive control (acarbose) with an IC50 value of 93.63 μM. Enzyme kinetic studies of compounds 18 and 19 revealed their competitive inhibition with Ki values of 3.93 and 1.80 μM, respectively. Computational studies demonstrated that compound 18 could be inserted into the original binding site (OBS) of α-glucosidase MAL12 and form multiple hydrophobic interactions with nearby amino acids, with the bromo group playing an essential role in enhancing the binding strength and stability at the OBS of the enzyme based on the quantum mechanical calculations using the fragment molecular orbital method. These findings provide valuable insights into the design of potent α-glucosidase inhibitors, which may have potential therapeutic applications in the treatment of diabetes and related diseases.