Semisynthetic Derivatives of Polygodial as α-Glucosidase and α-Amylase Inhibitors: In Vitro Evaluation, Molecular Docking and Molecular Dynamics Simulation.

Background: Polygodial (9), a drimane sesquiterpene dialdehyde from Drimys winteri, has not previously been examined against carbohydrate-hydrolyzing enzymes. Methods: Regioselective Wittig olefination at C12 gave the enoate 10; reduction of the remaining C11 aldehyde with NaBH4 was followed by spontaneous intramolecular conjugate addition, affording the annellated tetrahydrofuran 12a and the bridged ether 12b. Results: All three derivatives inhibited α-glucosidase and α-amylase more strongly than the parent compound. Compound 12a was the most active α-glucosidase inhibitor (IC50 = 53.98 ± 3.0 µM, against 90.36 ± 4.0 µM for acarbose) and, in docking, the only derivative to occupy the acarbose-binding site of the enzyme (-8.1 kcal/mol). However, this 12a-α-glucosidase pose was not maintained during the 200 ns simulations. The enoate 10 was the most active α-amylase inhibitor (IC50 = 42.32 ± 2.1 µM, against 78.24 ± 3.9 µM for acarbose; -8.5 kcal/mol). Over 200 ns of molecular dynamics, the 10-α-amylase complex remained associated, with binding attributed by MM-GBSA mainly to van der Waals and lipophilic terms. Conclusions: Converting the dialdehyde into an enoate or a cyclic ether increases carbohydrase inhibition and determines which of the two enzymes is preferentially inhibited.