New Dipterocarpol-Based Molecules with α-Glucosidase Inhibitory and Hypoglycemic Activity

Dammarane triterpenoids are affordable and bioactive natural metabolites with great structural potential, which makes them attractive sources for drug development. The aim of the study was to investigate the potency of new dipterocarpol derivatives for the treatment of diabetes. Two dammaranes (dipterocarpol and its 20(24)-diene derivative) were modified by a Claisen-Schmidt aldol condensation to afford C2(E)-arylidenes in good yields. The majority of the synthesized compounds exhibited an excellent-to-moderate inhibitory effect toward α-glucosidase (from S. saccharomyces), among them eight compounds showed IC₅₀ values less than 10 μM. 3-Oxo-dammarane-2(E)-benzylidenes (holding p-hydroxy- 3 l and p-carbonyl- 3 m substituents) demonstrated the most potent α-glucosidase inhibition with IC₅₀ 0.753 and 0.204 μM, being 232- and 857-times more active than acarbose (IC₅₀ 174.90 μM), and a high level of NO inhibition in Raw 264.7 cells with IC₅₀ of 1.75 and 4.57 μM, respectively. An in vivo testing of compound 3 m (in a dose of 20 mg/kg) on a model of streptozotocin-induced T1DM in rats showed a pronounced hypoglycemic activity, the ability to reduce effectively the processes of lipid peroxidation in liver tissue and decrease the excretion of glucose and pyruvic acid in the urine. Compound 3 m reduced the death of diabetic rats and preserved their motor activity.