Analysis of the antidiabetic potential of natural xanthones through the inhibition of α-amylase and α-glucosidase activities

Diabetes mellitus (DM) is a complex endocrine disorder associated with a state of hyperglycemia caused by the deficiency in the secretion of insulin and/or in the action of this pancreatic hormone. Thus, the control of postprandial blood glucose level via the inhibition of carbohydrate-hydrolyzing enzymes, such as α‐amylase and α‐glucosidase, is a consistent strategy for the management of type 2 DM and its related complications.1,2 In the past two decades, diversely functionalized xanthones, an important class of oxygen-containing heterocyclic compounds, have been recognized by scientific community for their interesting antidiabetic profile, exemplified by the number of studies developed in this area.3 Recent advances have been noticed in the inhibition of α-glucosidase activity by natural xanthones. However, the effects of this class of compounds on the activity of α-amylase enzyme is still scarce.1-3 As part of our on-going project, the main goal of the present study is to evaluate the inhibitory effects of a group of natural xanthones [mangiferin (1), α-mangostin (2) and γ-mangostin (3)] against both α‐amylase and α‐glucosidase enzymatic activity, using a spectrophotometric screening methodology.4,5 Acarbose was used as standard inhibitor for both assays. In addition, the study of the inhibition type for the two enzymes was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plots. The results showed that the studied xanthones exhibited a stronger inhibition against α-glucosidase when compared to α-amylase activity. Mangiferin (1) was not active against any enzyme, α-mangostin (2) was only able to inhibit the action of α-glucosidase, while γ-mangostin (3) inhibited both enzymes, being more active against α-glucosidase activity. In addition, the type of inhibition mechanism was also studied, and the results indicate a competitive type of inhibition for γ-mangostin (3) against α-amylase activity while the action of α-mangostin (2) and γ-mangostin (3) against α-glucosidase activity is through a non-competitive inhibition mechanism. The present work can open a promising area of research based on the design of novel xanthone derivatives for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 DM.The work was supported by UIBD/00690/2020, UIDB/50006/2020 and UID/DTP/04138/2020 with funding from FCT/MCTES through national funds, and by PTDC/MEDQUI/ 29241/2017–POCI-01-0145-FEDER-029241, with funding from FCT/MCTES through national funds, and “Programa Operacional Competitividade e Internacionalização” (COMPETE). Carina Proença acknowledges funding from FCT and MCTES through national funds and COMPETE, grant number PTDC/MED-QUI/29243/2017-POCI-01-0145-FEDER-029243. Marisa Freitas acknowledges her contract under the Scientific Employment Stimulus - Individual Call (CEEC Individual) 2020.04126.CEECIND/CP1596/CT0006