Design and synthesis of new flavonols as dual ɑ-amylase and ɑ-glucosidase inhibitors: Structure-activity relationship, drug-likeness, in vitro and in silico studies

Abstract In this study, a library of new intriguing flavonol derivatives (1–17) was designed and synthesized through a facile route involving Algar-Flynn-Oyamada reaction in a one-pot synthesis. The molecular structures of all newly synthesized compounds were unequivocally corroborated by different spectroscopic techniques such as FTIR, UV–Vis, 1H NMR and 13C NMR and mass spectrometry (EI-MS). All the synthesized analogs (1-17) were evaluated in vitro for their inhibitory potential against ɑ-amylase and ɑ-glucosidase enzymes. Interestingly, all the synthetic compounds displayed good to moderate inhibition potential with IC50 values ranging from 4.86 ± 1.39 to 265.61 ± 5.85 μM for a-amylase, and 70.57 ± 1.13 to 322.98 ± 4.43 μM for a-glucosidase in comparison to the standard acarbose (IC50 = 5.03 ± 9.44 μM for a-amylase and IC50 = 75.26 ± 0.15 μM for α-glucosidase). It is worth mentioning that amongst the series, the compounds 9 (IC50 = 4.86 ± 1.39 μM for a-amylase and IC50 = 70.57 ± 1.13 μM for α-glucosidase) and 14 (IC50 = 5.02 ± 1.35 for a-amylase and IC50 = 71.69 ± 5.85 μM for α-glucosidase) were found the most potent dual inhibitors, even more active than standard. Furthermore, the target compounds (1-17) exhibited moderate to good antioxidant activities. Molecular simulations studies were conducted to correlate the in vitro results and to identify the possible mode of binding interaction of ligands with the active site of enzymes. Moreover, molecular description was performed with the drug-likeness and bioactivity scores. The results showed that some compounds are in a linear correlation with Lipinski’s rule of five demonstrating good drug-likeness and bioactivity score for drug targets. Structure-activity relationships delivered useful insights towards this class of compounds, and thus paved the way to design novel analogs with improved potency.