Serratene triterpenoids from Lycopodium cernuum L. as α-glucosidase inhibitors: Identification, structure-activity relationship and molecular docking studies

Abstract

Phytochemical investigation of Lycopodium cernuum L. afforded seven undescribed serratene triterpenoids named 3β, 21β-dihydroxyserra-14-en-24-oic acid-3β-(5'-hydroxybenzoate) (1), 3β, 21β, 24-trihydroxyserrat-14-en-3β-(5'-hydroxyl benzoate) (2), 3β, 14α, 15α, 21β-tetrahydroxyserratane-24-methyl ester (3), 3β, 14α, 21β-trihydroxyserratane-15α-(4'-methoxy-5'-hydroxybenzoate)-24-methyl ester (4), 3β, 14α, 21β-trihydroxyserratane-15α-(4'-methoxy-5'-hydroxybenzoate) (5), 3β-hydroxy-21β-acetate-16-oxoserrat-14-en-24-oic acid (6), 3β, 21β-dihydroxy-16α, 29-epoxyserrat-14-en-24-methyl ester (7), together with eleven known compounds (8-18), whose chemical structures were elucidated through spectroscopic analysis of HRESIMS, 1D NMR, 2D NMR and comparison between the literature. All compounds were evaluated for their α-glucosidase inhibitory activity for the first time. The results showed that compounds 1, 2, 4, 5, 6, 10, 13, 15, and 16 were among the most potent α-glucosidase inhibitors, with IC₅₀ values ranging from 23.22 ± 0.64 to 50.65 ± 0.82 μM. Structure-activity relationship (SAR) studies indicated that the combined properties of the 5-hydroxybenzoate moiety at C-3, β-OH at C-21, COOH- at C-24, and Δ^14,15 groups enabled an increase in the α-glucosidase inhibitory effect. In addition, molecular docking studies showed that the potential inhibitors mainly interact with key amino acid residues in the active site of α-glucosidase through hydrogen bonds and hydrophobic forces.

Keywords: Lycopodium cernuum L. (Lycopodiaceae); Molecular docking; Serratene triterpenoids; Structure–activity relationship; α-Glucosidase inhibition.