Discovery, α-Glucosidase Inhibitory Activity, and Structural Optimization of the Alkaloids from Vanderbylia robiniophila SY636

α-Glucosidase inhibitory activity-guided isolation led to the discovery of ten alkaloids from the medicinal mushroom Vanderbylia robiniophila SY636, including six new compounds ((+)- 1a, (−)- 1b, (+)- 2a, (−)- 2b, 3, and (+)- 4a ) and four newly reported natural products ((−)- 4b and 5 – 7 ). Compounds (+)- 1a, (−)- 1b, (+)- 2a, and (−)- 2b possess a unique lactam–furan ring system, whereas 3 features a rare tetrahydrobenzo[ c ]oxepine–furan ring system. (+)- 1a, (−)- 1b, (+)- 4a, and (−)- 4b exhibited notable α-glucosidase inhibitory activities, with IC 50 values of 160–330 μM (acarbose as the positive control, IC 50 = 660 μM). Guided by docking results of bioactive compounds with α-glucosidase, derivatives D1 – D28 were designed and synthesized, among which D15 and D19 exhibited stronger activities (IC 50 = 28 and 130 μM). Molecular docking and kinetic studies suggested that D15 and D19 interact with α-glucosidase at a single binding site, exhibiting an uncompetitive or mixed type of inhibition mechanism. D19 also exhibited notable antioxidant activity (IC 50 = 35 μM), comparable to l -ascorbic acid, suggesting its dual role in combating the development of diabetes. This study provides a foundation for the development of natural medicines from V. robiniophila and offers valuable guidance for future structural optimization toward the discovery of more potent and safer antidiabetic agents.