ABSTRACT
The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two ß-glucosidase (almond) inhibitors (14b,f) in the low µM range. The additional biological analysis of 14b,f towards ß-glucocerebrosidase (human lysosomal ß-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards ß-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver ß-glucosidase as neutral hydrolase. In contrast to what was observed for ß-glucosidase inhibition, the coffee bean α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase.
Subject(s)
Enzyme Inhibitors/pharmacology , Pyrrolidines/pharmacology , Small Molecule Libraries/pharmacology , Triazoles/pharmacology , alpha-Galactosidase/antagonists & inhibitors , beta-Glucosidase/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , alpha-Galactosidase/metabolism , beta-Glucosidase/metabolismABSTRACT
The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).