Structure–activity relationships in aminocyclopentitol glycosidase inhibitors

Abstract

Aminocyclopentitol analogs of β-D-glucose, β-D-galactose and α-D-galactose bearing alkyl substituents as aglycon mimics on the amine function were prepared and tested for inhibition of various glycosidases. N-benzyl-β-D-gluco derivatives 1–4 and N-benzyl-β-D-galacto derivative 5 inhibited β-galactosidase and β-glucosidase. N-benzyl-α-D-galacto aminocyclopentitol 6 strongly inhibited α-galactosidase. The inhibitory activities observed were generally stronger compared to those of their primary amine analogs. A structure–activity relationship analysis was carried out including data from thirty-five different aminocyclopentitol glycosidase inhibitors. The strongest inhibitions reported for any enzyme were associated with a perfect stereochemical match between aminocyclopentitol and glycosidase, including the α- or β-configuration of the amino-group corresponding to the enzyme's anomeric selectivity.