Ellagitannins from Punica granatum Stem and Pericarpium: Mechanistic Insights into PTP1B Inhibition and Evaluation of α-Glucosidase Inhibition and Antioxidant Activity

A phytochemical investigation of Punica granatum L. stems and pericarpium yielded five new polyphenols (punicagranols A–E) and 47 known compounds. Antioxidant activity evaluated by DPPH assay indicated that compounds 13 and 25–33 exhibited strong radical-scavenging activity (IC₅₀< 5 μM), outperforming ascorbic acid. Structure–activity relationship (SAR) analysis linked this activity to hydroxyl group distribution and the presence of hexahydroxydiphenoyl and galloyl moieties. Compounds were also tested for inhibition of α-glucosidase and PTP1B, enzymes involved in type 2 diabetes. Notably, compounds 25, 29, and 33 exhibited potent dual inhibition, exceeding reference inhibitors. Kinetic and docking studies revealed that compound 25 acts as a competitive inhibitor, while compounds 29 and 33 inhibit PTP1B noncompetitively. SAR analysis further emphasized the importance of glucose core stereochemistry and galloyl substitution. These findings highlight ellagitannins as promising antidiabetic leads and support the use of P. granatum as a valuable source of health-promoting food.