Cyclic Amidine Sugars as Transition-State Analogue Inhibitors of Glycosidases: Potent Competitive Inhibitors of Mannosidases

A series of monocyclic glycoamidines bearing different exocyclic amine, alcohol, or alkyl functionalities and bicyclic amidines derived from d-glucose and d-mannose were synthesized and tested as inhibitors of various glycosidases. All the prepared compounds demonstrated good to excellent inhibition toward glycosidases. In particular, the biscationic d-mannoamidine 9b bearing an exocyclic ethylamine moiety proved to be a selective competitive inhibitor of α- and β-mannosidases (K_i = 6 nM) making it the most potent inhibitor of these glycosidases reported to date. A favorable B_2,5 boat conformation might explain the selectivity of mannosidase inhibition compared to other glycosidases.