A pH-Dependent Curcumin-Iminosugar Hybrid Promotes GCase Enhancement and Reactive Oxygen Species Reduction.

Gaucher disease and Parkinson's disease are characterized by β-glucocerebrosidase (GCase) dysfunction and increased oxidative stress. Here, we report two multifunctional hybrids that combine an iminosugar-based pharmacological chaperone scaffold with curcumin- or ferulic acid-derived antioxidant motifs. The curcumin-iminosugar hybrid 2 exhibits pH-dependent GCase modulation, enhanced GCase activity under lysosomal conditions, enhanced enzyme activity in L444P Gaucher and wild-type fibroblasts, and reduced intracellular reactive oxygen species (ROS) levels. By integrating GCase enhancement and redox modulation within a single molecular framework, compound 2 represents a promising lead for Gaucher disease and GCase-related synucleinopathies.