Selenoureido-N-alkyl-3,4,5-trihydroxypiperidines: probing their dual-target role in Gaucher disease

The design and synthesis of a novel class of selenoureido-iminosugar compounds that uniquely combine antioxidant properties with pharmacological chaperone activity are reported. These derivatives feature a 3,4,5-trihydroxypiperidine iminosugar core linked via nine- or twelve‑carbon alkyl chains to N-aryl selenoureido groups. By simultaneously targeting oxidative stress and lysosomal β-glucocerebrosidase (GCase) dysfunction, this dual-action strategy addresses two key pathological hallmarks of Gaucher disease. These compounds were evaluated for the first time on human GCase and on fibroblasts derived from Gaucher patients carrying clinically relevant GBA1 variants. Notably, one of the newly synthesized compounds significantly restored GCase activity in patient-derived cells and induced a ∼60% reduction in intracellular ROS levels, further supporting its bifunctional therapeutic potential. This study introduces an innovative dual-action molecular scaffold for addressing key pathological mechanisms in Gaucher disease and related neurodegenerative conditions.