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

A phytochemical investigation of <i>Punica granatum</i> L. stems and pericarpium yielded five new polyphenols (punicagranols A-E) and 47 known compounds. Antioxidant activity evaluated by DPPH assay indicated that compounds <b>13</b> and <b>25</b>-<b>33</b> 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 <b>25</b>, <b>29</b>, and <b>33</b> exhibited potent dual inhibition, exceeding reference inhibitors. Kinetic and docking studies revealed that compound <b>25</b> acts as a competitive inhibitor, while compounds <b>29</b> and <b>33</b> 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 <i>P. granatum</i> as a valuable source of health-promoting food.