α-Glucosidase Inhibitors from the Leaves of <i>Cannabis sativa</i>: Structure–Activity Relationship, Kinetic Investigation, and Molecular Docking

<i>Cannabis sativa</i> L. is a valuable agricultural crop, extensively utilized in various fields and comprising diverse chemical constituents. In preliminary experiments for rat intestinal α-glucosidase inhibition, the methanolic extract of <i>Cannabis sativa</i> demonstrated potential for inhibiting maltase and sucrase. Bioassay-guided isolation led to 30 metabolites, including five new cannabinoids (<b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>30</b>) and four new spiroindans (<b>5</b>, <b>6</b>, <b>10</b>, <b>11</b>). Their structures were elucidated using spectroscopic techniques such as NMR, and absolute configurations were determined by Mosher's method. Cannabinoids were the main contributors to inhibitory potency (IC₅₀: 0.09-0.8 mM), while spiroindans and simple phenolics showed lower activity (IC₅₀: 1.0-2.2 mM). 8-Hydroxycannabinol (<b>18</b>) was the most potent inhibitor retarding the enzymes through a noncompetitive mechanism. Molecular dynamics simulations of compounds <b>15</b> and <b>18</b> showed that hydrogen bonding between phenolic hydroxyl groups and specific amino acid residues at the allosteric site was essential for strong α-glucosidase binding.