Exploring the Antidiabetic Potential of Novel Benzimidazole Analogs: Synthesis, Molecular Docking and DPP-4 Activity Evaluation

Dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as well-tolerated, safe antidiabetic medications. This work aimed to design and synthesize a series of benzimidazole compounds (SS1A1-SS1A6 and SS2A1-SS2A6) as possible DPP-IV inhibitors. The compounds were characterized with FT-IR, 1H NMR, 13C NMR and mass spectrometry. Molecular docking, ADME analysis and Lipinski’s drug-likeness rules were among the in silico experiments used to assess their binding affinity to DPP-4 and forecast their pharmacokinetic characteristics. In vitro DPP-4 inhibition tests were used to determine the biological activity of compounds and the findings indicated that none of them broke any of the main drug-likeness requirements. According to the molecular docking simulations, several derivatives showed stronger interactions and hydrogen bonds with ligands than the natural protein (PDB ID: 5Y7H). The most effective synthetic compound for inhibiting DPP-4 was compound SS2A2, which had an activity value of 1.68 µg/mL, much lower than the control 11.56 µg/mL. Based on both in vitro and in silico validation, these results imply that compound SS2A2 is a good candidate for additional optimization as a DPP-4 inhibitor for antidiabetic treatment.