Structure–activity relationships in a series of C2-substituted gluco-configured tetrahydroimidazopyridines as β-glucosidase inhibitors

Inhibition of glycoside hydrolases has widespread application in treatment of diabetes, viral infections, lysosomal storage diseases and cancers. Gluco-configured tetrahydroimidazopyridines are the most potent β-glucosidase inhibitors reported to date. Using transition state mimic strategy, a series of C2-substituted gluco-configured tetrahydroimidazopyridines were designed and synthesized. Compounds 3 (Ki = 0.64 nM) and 5 (Ki = 0.58 nM) showed stronger inhibitory potency against β-glucosidase. Maestro 9.1 was used to study the structure–activity relationships by docking the compounds into the β-glucosidase active sites.

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