Antidiabetic Activity of Compounds Isolated From Zanthoxylum mildbraedii: An In Vitro α-Amylase Inhibition and In Silico Analysis.

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from insulin dysfunction or resistance. The global rise in diabetes prevalence has intensified the search for novel therapeutic agents with improved efficacy and minimal side effects. Natural products offer a promising reservoir of bioactive compounds with potential antidiabetic properties. In this study, four secondary metabolites lupeol (1), fagaramide (2), sesamin (3), and N-isobutylcinnamamide (4) were isolated from the stem bark of Zanthoxylum mildbraedii. Their α-amylase inhibitory activities were evaluated in vitro, alongside in silico docking and pharmacokinetic profiling. All four compounds exhibited moderate α-amylase inhibition (IC50 = 16.38-27.73 mM) compared to the standard drug acarbose (IC50 = 11.98 ± 1.07 mM). Kinetic analysis revealed distinct modes of inhibition: lupeol and sesamin exhibited noncompetitive inhibition, fagaramide showed mixed-type inhibition, and N-isobutylcinnamamide demonstrated competitive inhibition. Molecular docking against human α-amylase (PDB ID: 1XH2) supported these findings, with favorable binding affinities (-8.8 to -6.9 kcal/mol). Furthermore, in silico ADME profiling indicated that all compounds adhered to Lipinski's rule of five, exhibited acceptable hydrogen bonding characteristics, favorable topological polar surface areas, and good predicted GI absorption and oral bioavailability. These findings suggest that the isolated compounds from Z. mildbraedii possess promising α-amylase inhibitory potential and drug-like properties, indicating their potential as lead candidates for further development of natural antidiabetic therapeutics. Their favorable pharmacokinetic attributes and multimodal inhibition mechanisms highlight the significance of this study in contributing to the discovery of safer, plant-derived agents for diabetes management.