Dual target approach for the treatment of Gaucher disease: new iminosugar pharmacological chaperones with antioxidant/anti-inflammatory properties

The design and synthesis of multitarget directed ligands represents one of the most attractive and challenging fields in medicinal chemistry research. Nitrogen-containing glycomimetics, such as iminosugars, have proven to be inhibitors of glycosidases and glycosyltransferases. More recently, these compounds have been introduced as therapeutic agents towards lysosomal storage disorders (LSDs), acting as pharmacological chaperones (PCs). PCs are small molecules able to rescue the activity of mutated enzymes. In the context of LSDs, they favor the correct folding of the enzymes and facilitate their translocation to the lysosomes when used at subinhibitory concentration. In this work, we report a series of trihydroxypiperidine iminosugars bearing different antioxidant or anti-inflammatory moieties as potential bifunctional agents for the treatment of Gaucher disease (GD), starting from low-cost D-mannose. GD is the most prevalent LSD, caused by mutation in the GBA gene encoding for lysosomal β-glucocerebrosidase (GCase), which is responsible for the hydrolysis of glucosylceramide. The new compounds are potentially able to mend GCase dysfunction while reducing the severe oxidative stress/inflammatory state observed in GD patients. Since GBA mutations are also known as the most recurrent genetic risk factors for Parkinson disease (PD), these novel compounds are interesting for the treatment of PD as well. The synthesis of the new bifunctional compounds and their biological evaluation towards GCase will be presented.