Multifunctional quinoline-based hydrazones as promising antidiabetic agents: experimental and computational insights

A new library of quinoline-based hydrazone analogues (7a-7j) was designed and synthesized to evaluate their potential as multifunctional antidiabetic agents. In contrast to earlier quinoline derivatives primarily developed for single-enzyme inhibition, the present series incorporates a quinoline scaffold with a thiocarbohydrazide-derived hydrazone linker and diverse aryl/heteroaryl substituents to investigate a multitarget profile involving α-glucosidase, α-amylase, and PPAR-γ. Biological evaluation showed low-micromolar inhibitory activity against key carbohydrate-metabolizing enzymes. Compounds 7e and 7h exhibited the most potent α-glucosidase inhibition (IC₅₀: 18.55 ± 2.34 and 20.73 ± 0.37 μM, respectively), with activity comparable to acarbose (IC₅₀: 16.53 ± 0.39 μM). Compound 7g showed the strongest α-amylase inhibition (IC₅₀: 7.85 ± 1.92 μM). In addition, compounds 7b and 7f significantly enhanced PPAR-γ transcriptional activity in L6 myotubes, suggesting potential insulin-sensitizing effects. Molecular docking and molecular dynamics simulations supported stable ligand-protein interactions with key catalytic residues across all targets. In silico ADMET analysis indicated acceptable permeability and oral absorption; however, moderate lipophilicity and limited aqueous solubility of some analogues may require further optimization. Overall, these findings highlight quinoline-based hydrazones as promising multitarget scaffolds for further in vivo evaluation.