Novel Pyridazine–Hydrazone Derivatives: Design, Synthesis, Characterization, In Vitro α‐glucosidase and α‐amylase Inhibition, and In Silico Studies

ABSTRACT

This study involved the synthesis, characterization, and toxicity prediction of nine novel pyridazine‐hydrazone analogs ( 3a–i ) to investigate their inhibitory activity against α‐amylase and α‐glucosidase enzymes as potential antidiabetic agents using in vitro assays. In addition, in silico molecular docking was conducted to evaluate the binding interactions of these analogs with the target enzymes, while physicochemical and pharmacokinetic properties were predicted using the ADMET2.0 web server. The in vitro assays demonstrated significant α‐amylase inhibitory activity (except for compounds 3a and 3b ), with IC ₅₀ values ranging from 61.21 ± 0.78 to 209.40 ± 2.98 µM, compared with the standard drug acarbose (IC ₅₀  = 126.5 ± 0.02 µM). All compounds also exhibited significant α‐glucosidase inhibitory activity, with IC ₅₀ values ranging from 19.91 ± 0.12 to 204.3 ± 1.76 µM, compared with acarbose (IC ₅₀  = 98.12 ± 0.01 µM). Notably, compounds 3e and 3h showed the strongest α‐amylase inhibition, whereas 3c , 3g , and 3i were the most potent α‐glucosidase inhibitors. Molecular docking revealed binding energies ranging from −7.6 to −9.2 kcal/mol for α‐amylase (PDB ID: 4GQR) and −6.0 to −8.0 kcal/mol for α‐glucosidase (PDB ID: 5NN5), supporting their potential as promising α‐amylase and α‐glucosidase inhibitors.