Discovery of Novel Pyrrolidine-Based Chalcones as Dual Inhibitors of α-Amylase and α-Glucosidase: Synthesis, Molecular Docking, ADMET Profiles, and Pharmacological Screening

A series of chalcones containing a pyrrolidine moiety were synthesized to examine their <i>in vitro</i> α-amylase and α-glucosidase inhibitory activities, for the treatment of <i>Diabetes mellitus</i>, which is one of the most dangerous and rapidly increasing disorders of today. Compound <b>3</b> exhibited an excellent dual inhibitory effect with an IC₅₀ value of 14.61 ± 0.12 μM against α-amylase, and with an IC₅₀: 25.38 ± 2.09 μM against α-glucosidase. The <i>in vitro</i> cytotoxic effects of all compounds against nonsmall lung cancer (A549) and bronchial epithelial normal (BEAS-2B) cell lines were also evaluated. Compound <b>5</b> (IC₅₀: 82.20 μM) and compound <b>8</b> (IC₅₀: 59.96 μM) showed better cytotoxic activity than cisplatin against A549 (IC₅₀: 84.39 μM) cells. Furthermore, these compounds had no harmful effect on healthy BEAS-2B cells at the determined IC₅₀ values. Moreover, the molecular docking and molecular dynamics simulation analysis revealed that all synthesized compounds exhibited stronger binding affinities toward α-glucosidase and α-amylase compared to the positive control acarbose.