The work was supported by UIBD/00690/2020 and UIDB/50006/2020 with funding from FCT/MCTES through national
funds, and by EXPL/MED-QUI/0815/2021, with funding from FCT. 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.
Xanthones are oxygen-containing heterocyclic compounds that exhibit a wide range of biological and
pharmacological properties. Some natural and synthetic derivatives have been identified for their antidiabetic
profile, mainly as α-glucosidase inhibitors. However, studies concerning the inhibition of both
carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase are scarce. Thus, in order to identify
some of these dual-target antidiabetic agents, a series of new synthetic xanthones were evaluated
together with their commercial parents mangiferin (4), α-mangostin (5) and γ-mangostin (6). The results
showed that xanthones exhibited a systematic stronger inhibition against α-glucosidase rather than for
α-amylase. Derivatives 2c, 3a and 3b, bearing one catechol moiety, were the most active inhibitors of
α-amylase, while xanthones 2c, 3b and 3c were the most active against α-glucosidase activity, with IC50
values lower than 10 μM. These findings suggest that the substitution pattern of the xanthone scaffold
modulated the inhibitory activity of these compounds, and some structure–activity relationships could be
established for both assays. In addition, the type of inhibition was also studied, and the results indicate a
competitive type of inhibition for α-amylase activity by xanthones 2c, 3b, 3c and γ-mangostin (6). On the
other hand, non-competitive inhibition mechanisms can be ascribed for all xanthones 1–6 against
α-glucosidase. The present work can open a promising area of research based on the design of novel
xanthone derivatives, based on natural ones, for targeting key enzymes involved in glucose metabolism
and therefore in the management of type 2 diabetes mellitus.
