Assessment of the inhibitory potential of tenofovir ester conjugates against α-glucosidase activity using in-vitro and in-silico methods

Abstract: Background: Alpha-glucosidase is an essential enzyme in carbohydrate metabolism, responsible for hydrolyzing disaccharides into monosaccharides (glucose). Inhibition of this enzyme is an effective approach to control postprandial hyperglycemia in type 2 diabetes. Previous studies have reported that some antiviral agents, including tenofovir, exhibit potent α-glucosidase inhibitory activity comparable to that of acarbose. Objectives: This study employed both in-vitro and in-silico methods to design, synthesize and assess new tenofovir ester conjugates as potential α-glucosidase inhibitors. Method: In this study, 22 ester derivatives of tenofovir were synthesized by masking the hydroxyl group with hydroxyl, amino and phenolic groups, as well as with fatty acid chains. The synthesized compounds were thoroughly characterized using mass spectrometry, ¹H-NMR, ¹³C-NMR, NOESY, COSY, HSQC, HMBC, UV and IR spectroscopy. To assess in-vitro α-glucosidase activity, an enzyme from yeast (Saccharomyces cerevisiae) was used. Results: All synthesized derivatives (2–22) demonstrated significant α-glucosidase inhibition, with IC₅₀ values ranging from 7.80 ± 0.42 to 342.59 ± 2.19 µM, exhibiting greater potency than the standard inhibitor acarbose (IC₅₀ = 875.75 ± 2.09 µM). Molecular docking studies supported these findings, showing binding energies ranging from −9.1 to −11.7 kcal/mol, greater than those achieved with acarbose (−8.4 kcal/mol). Among them, compounds 2 and 6 displayed the highest inhibitory activities (IC₅₀ = 10.50 ± 0.46 µM and 7.80 ± 0.42 µM, respectively) with strong binding affinities (−11.5 and −11.7 kcal/mol). Conclusion: The findings suggest that tenofovir-derived ester compounds, particularly 2 and 6, are promising candidates for the continued development of potent α-glucosidase inhibitors for the management of type 2 diabetes.