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

Abstract

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 co ff ee bean α -galactosidase inhibitor (IC 50 = 0.37 μ M, K i = 0.12 μ M) that has also showed inhibition against human lysosomal α -galactosidase ( α -Gal A, IC 50 = 5.3 μ M, K i = 4.2 μ M).