α-Glucosidase Inhibitors from the Leaves of Cannabis sativa: Structure-Activity Relationship, Kinetic Investigation,...

Cannabis sativa 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 Cannabis sativa demonstrated potential for inhibiting maltase and sucrase. Bioassay-guided isolation led to 30 metabolites, including five new cannabinoids (1, 2, 3, 4, 30) and four new spiroindans (5, 6, 10, 11). 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 (18) was the most potent inhibitor retarding the enzymes through a noncompetitive mechanism. Molecular dynamics simulations of compounds 15 and 18 showed that hydrogen bonding between phenolic hydroxyl groups and specific amino acid residues at the allosteric site was essential for strong α-glucosidase binding.