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

Suitably substituted cinnamamides (3a-n) were successfully synthesized and tested for alpha-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 mu M), with IC50 values ranging from 44.43 +/- 5.7 to 91.14 +/- 11.4 mu M. Their alpha-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 alpha-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 alpha-glucosidase, namely Asp469 and Asp568. Overall, these cinnamamides show potential as lead structures for further optimization as alpha-glucosidase inhibitors.