Influence of the aromatic substituent on the α-glucosidase inhibitory activity of D-ribose derived 1,2,3-triazoles

International Diabetes Federation estimates that 1 in 9 adults aged 20-79 years is living with diabetes; more than 90% of these cases correspond to type 2 diabetes.¹ One therapeutic strategy for controlling postprandial hyperglycemia is the inhibition of α-glucosidase. Most known α-glucosidase inhibitors are glycomimetics that resemble the natural substrates of the enzyme, which facilitates their binding to the active site. Among them, carbohydrate-derived 1,2,3-triazoles have previously been reported as α-glucosidase inhibitors.²

On this basis, a new set of D-ribose-derived triazoles was synthesized and characterized. These compounds were designed to share the same carbohydrate-triazole core while differing only in the aromatic substituent. D-Ribose was protected as its 2,3-O-isopropylidene methyl glycoside leaving a free hydroxyl group at C-5. The protected sugar was then converted into the corresponding tosylate, which underwent nucleophilic displacement with azide to afford the 1,3-dipole. The dipolarophiles were prepared by O-propargylation of the corresponding phenols or benzyl alcohol with propargyl bromide. The target compounds were obtained in high yields through CuAAC reaction of both precursors in water/dichloromethane, using copper(II) sulfate and sodium ascorbate as the catalytic system.

All products were evaluated against maltase from Saccharomyces cerevisiae and murine α-glucosidase following previously reported procedures.³ The most active compound, derivative of pentafluorophenol, showed an IC₅₀ value of 25.63 µM, comparable to that of the reference inhibitor quercetin (IC₅₀ = 20 µM), while showing only slight inhibition of the murine enzyme (around 10%). The rest of the synthesized compounds showed negligible inhibition of the enzyme, with an IC₅₀ > 500 µM.

1. International Diabetes Federation, 2026. https://idf.org/

2. Ferreira, S. B. et al. J. Med. Chem. 2010, 53, 2364–2375.

3. Matsui, T. et al. Biosci. Biotechnol. Biochem. 1996, 60 (12), 2019–2022.