Synthesis, α-glucosidase inhibitory activity, and molecular docking of cinnamamides

Suitably substituted cinnamamides (3a-n) were successfully synthesized and tested for α-glucosidase inhibitory activity. Nine of the synthesized cinnamamides (3a-f, k-m) displayed moderate inhibitory activity, which was better than acarbose (IC₅₀ = 185.00 ± 9.4 µM), with IC₅₀ values ranging from 44.43 ± 5.7 to 91.14 ± 11.4 µM. Their α-glucosidase inhibitory activity greatly depended on their structure with electron-withdrawing groups on the cinnamoyl aromatic ring causing increased inhibition activity. According to the in vitro assay results, compound 3b with p-dimethylamino on the cinnamoyl ring has the best α-glucosidase inhibitory activity. The new synthesized cinnamamides (3b-i) showed acceptable physicochemical and pharmacokinetics characteristics with little toxicity indicating their potential use as lead drug candidates. Molecular docking studies of compound 3b (binding energy −8.33 kcal/mol) revealed that it interacted with His626 and two catalytic residues of α-glucosidase, namely Asp469 and Asp568. Overall, these cinnamamides show potential as lead structures for further optimization as α-glucosidase inhibitors. Graphical Abstract: [Figure not available: see fulltext.]