An Arylbenzofuran, Stilbene Dimers, and Prenylated Diels-Alder Adducts as Potent Diabetic Inhibitors from Morus bombycis Leaves.

Morus bombycis has a long history of usage as a treatment for metabolic diseases, especially, diabetes mellitus (DM). Thus, we aimed to isolate and evaluate bioactive constituents derived from M. bombycis leaves for the treatment of DM. According to bioassay-guided isolation by column chromatography, eight compounds were obtained from M. bombycis leaves: two phenolic compounds, p -coumaric acid ( 1 ) and chlorogenic acid methyl ester ( 2 ), one stilbene, oxyresveratrol ( 3 ), two stilbene dimers, macrourin B ( 4 ) and austrafuran C ( 6 ), one 2-arylbenzofuran, moracin M ( 5 ), and two Diels-Alder type adducts, mulberrofuran F ( 7 ) and chalcomoracin ( 8 ). Among the eight isolated compounds, the anti-DM activity of 3 - 8 (which possess chemotaxonomic significance in Morus species) was evaluated by inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation as well as by scavenging peroxynitrite (ONOO - ), which are crucial therapeutic targets of DM and its complications. Compounds 4 and 6 - 8 significantly inhibited α-glucosidase, PTP1B, and HRAR enzymes with mixed-type and non-competitive-type inhibition modes. Furthermore, the four compounds had low negative binding energies in both enzymes according to molecular docking simulation, and compounds 3 - 8 exhibited strong antioxidant capacity by inhibiting AGE formation and ONOO - scavenging. Overall results suggested that the most active stilbene-dimer-type compounds ( 4 and 6 ) along with Diels-Alder type adducts ( 7 and 8 ) could be promising therapeutic and preventive resources against DM and have the potential to be used as antioxidants, anti-diabetic agents, and anti-diabetic complication agents.