UPLC-QToF-MS/MS Profiling and Computational Analysis of Xanthone Compounds from Mangifera indica L. Leaves as Potential Inhibitors of Diabetic Enzymes

Abstract

Natural products are a vital reservoir for antidiabetic drug discovery, yet the diversity of xanthones in Mangifera indica leaves has not been systematically explored. This study aimed to characterize the bioactive constituents in M. indica through UPLC-QTOF-MS/MS profiling, integrated with in silico molecular docking to assess their inhibitory potential against α-glucosidase, α-amylase, and dipeptidyl peptidase IV (DPP-IV), enzymes central to postprandial glucose regulation. A total of five major xanthones were identified, including mangiferin, isomangiferin, 1,3,5,6-tetrahydroxyxanthone-C-4-β-D-glucopyranoside, mangiferin gallate, and isomangiferin gallate. Docking simulations revealed strong predicted binding affinity, with mangiferin gallate demonstrating the highest interaction with α-amylase and DPP-IV, and 1,3,5,6-tetrahydroxyxanthone-C-4-β-D-glucopyranoside exhibiting strong predicted binding affinity against α-glucosidase. Additionally, the ADMET predictions revealed a mixed profile: while all compounds showed no hepatotoxicity, no skin sensitization, and favorable CYP inhibition profiles, some compounds exhibited positive Ames toxicity predictions (mangiferin, isomangiferin, and isomangiferin gallate), all compounds were predicted as hERG II inhibitors, and intestinal absorption values were relatively low (31.8–52.9%). These findings suggest that while the compounds have promising safety aspects, further structural optimization may be required to address their pharmacokinetic limitations. M. indica leaves can be considered a promising source of xanthone-based inhibitors, and the molecular scaffolds identified represent promising candidates for further experimental evaluation as antidiabetic agents.