Discovery of a Potent α-Galactosidase Inhibitor by in Situ Analysis of a Library of Pyrrolizidine–(Thio)urea Hybrid Molecules Generated via Click Chemistry

The parallel synthesis of a 26-membered-library of aromatic/aliphatic-(thio)urea-linked pyrrolizidines followed by in situ biological evaluation toward α-galactosidases has been carried out. The combination of the (thio)urea-forming click reaction and the in situ screening is pioneer in the search for glycosidase inhibitors and has allowed the discovery of a potent coffee bean α-galactosidase inhibitor (IC50 = 0.37 μM, Ki = 0.12 μM) that has also showed inhibition against human lysosomal α-galactosidase (α-Gal A, IC50 = 5.3 μM, Ki = 4.2 μM).