Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of α-l-fucosidase

Abstract

Bioisosteric modification of known fucosidase inhibitors A and B, resulted in three new types of molecules, 4b, 5c and 6a (belonging to furopyridinedione, thiohydantoin and hydantoin chemotypes) that could potentially bind to α-l-fucosidase (bovine kidney origin). Molecular docking revealed and compared the putative binding interaction between 4b, 5c and 6a with A and B against the active site of a homology model of α-l-fucosidase. Based on this initial investigation, design and synthesis of a library of small molecules based on furopyridinedione, thiohydantoin and hydantoin, followed by their in vitro screening against α-l-fucosidase (bovine kidney origin) generated a potent inhibitor (compound 4e) with IC50 of ∼0.7 μM. Compound 4e possessed no cytotoxic properties when tested against healthy mammalian COS-1 cells. Reaction kinetics study suggested it to be a mixed inhibitor. Finally compounds 4a, b, e and f, bearing the furopyridinedione motif also exhibited substantial inhibition of the proliferation of MCF 7 breast cancer cells.