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

α-Glucosidase inhibitory activity-guided isolation led to the discovery of ten alkaloids from the medicinal mushroom <i>Vanderbylia robiniophila</i> SY636, including six new compounds ((+)-<b>1a</b>, (-)-<b>1b</b>, (+)-<b>2a</b>, (-)-<b>2b</b>, <b>3</b>, and (+)-<b>4a</b>) and four newly reported natural products ((-)-<b>4b</b> and <b>5</b>-<b>7</b>). Compounds (+)-<b>1a</b>, (-)-<b>1b</b>, (+)-<b>2a</b>, and (-)-<b>2b</b> possess a unique lactam-furan ring system, whereas <b>3</b> features a rare tetrahydrobenzo[<i>c</i>]oxepine-furan ring system. (+)-<b>1a</b>, (-)-<b>1b</b>, (+)-<b>4a</b>, and (-)-<b>4b</b> exhibited notable α-glucosidase inhibitory activities, with IC₅₀ values of 160-330 μM (acarbose as the positive control, IC₅₀ = 660 μM). Guided by docking results of bioactive compounds with α-glucosidase, derivatives <b>D1</b>-<b>D28</b> were designed and synthesized, among which <b>D15</b> and <b>D19</b> exhibited stronger activities (IC₅₀ = 28 and 130 μM). Molecular docking and kinetic studies suggested that <b>D15</b> and <b>D19</b> interact with α-glucosidase at a single binding site, exhibiting an uncompetitive or mixed type of inhibition mechanism. <b>D19</b> also exhibited notable antioxidant activity (IC₅₀ = 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 <i>V. robiniophila</i> and offers valuable guidance for future structural optimization toward the discovery of more potent and safer antidiabetic agents.