Antidiabetic and Antioxidant Molecules of Ficus tikoua and their Combined Effect: Bioassay-Guided Isolation, In Vitro and In Silico Analysis.

Ficus tikoua has high medicinal and edible value. Our previous study had demonstrated its antidiabetic properties, but the specific active molecules and their mechanisms remained unclear. In this study, five active compounds, namely marmesin glycoside (1), quercetin (2), quercetin 3-O-β-D-glucuronide-6''-methyl ester (3), (-)-epicatechin (4), (+)-epicatechin (5), were isolated by bioassay-guided method and identified. Compounds 1-5 displayed varying degrees of efficacy (IC₅₀ = 3.80-79.58 μM) and affinity (6.3-7.7 kcal/mol) on α-glucosidase. This was the first report that compound 1 exhibited the significant inhibitory activity on α-glucosidase (IC₅₀ = 3.80 μM) through a mixed inhibition mode, engaging with the residues GLY228 and ASN301. Additionally, compounds 1 and 2 showed the effect on promoting glucose uptake in 3T3-L1 adipocytes. Compounds 2-5 all showed potent effects in DPPH, ABTS, FRAP and DNA oxidative damage assays. Among them, compound 5 exhibited the strongest antioxidant activity for DPPH, ABTS, FRAP (10.56 μM, 4.34 mol Trolox/mol and 1.54 mol Trolox/mol, respectively), and compounds 3 and 5 (4 μM) demonstrated potent DNA protective effect. When combined in binary form, compounds 1 and 4 (FICI = 0.23), and compounds 4 and 5 (FICI = 0.47) displayed synergistic effects. This study revealed that Ficus tikoua could be used as a functional food, and the active compounds and combinations could serve as complementary therapeutic strategies for diabetes.