Toward marine inspired multitarget drugs for diabetes mellitus and its complications: design and synthesis of novel dual Protein Tyrosine Phosphatase 1B and Aldose Reductase ligands

Protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes are two emerging targets differently involved in the onset of type 2 diabetes mellitus (T2DM). Diabetes mellitus is a complex disease and is one of the leading causes of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. The opportunity to design inhibitors capable to bind orthosteric and allosteric regions of both PTP1B and AR is a promising tool for the discovery of new designed multiple ligands for T2DM treatment. Marine environment offers an enormous pool of chemical structures with uncommon and different structural motifs with a wide range of pharmaceutical applications. Phosphoeleganin, a marine-derived phosphorylated polyketide, has been identified as novel dual inhibitor of PTP1B/AR. Therefore, in order to gain further insights into structural requirements for dual PTP1B/AR inhibition and to develop the identified natural hit to a promising lead candidate, a fragment-based approach inspired by phosphoeleganin has been performed. The development of a versatile and efficient synthetic protocol was carried out due to effectively generate a small library of triol derivatives inspired to the functionalized polyol portion of phosphoeleganin. All the prepared synthetic simplified analogues have been tested for the inhibition of both enzymes and preliminary SAR studies have been performed. The obtained results evidenced that fragmentation of the molecule caused the loss of the activity on AR enzyme; moreover, a new phosphorylated triol with a potent and selective inhibitory activity against PTP1B, has been identified, encouraging the further investigation of other structural motifs of 1 in search of new and more potent multitarget inhibitors.