Extending the investigation of 4-thiazolidinone derivatives as potential multi-target ligands of enzymes involved in diabetes mellitus and its long-term complications: A study with pancreatic α-amylase

Diabetes mellitus is a multifactorial disease, which is frequently complicated by the development of hyperglycaemia-induced chronic complications. The therapy of diabetes mellitus often requires combinations of two or more drugs in order both to control glycaemic levels and to prevent hyperglycaemia-induced dangerous affairs. The application of multi-target agents, which are able to control simultaneously several pathogenic mechanisms, represents a useful alternative and, in fact, their discovery is a pursued aim of the research. Some (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic acids, which we had previously reported as inhibitors of selected enzymes critically implicated in diabetes mellitus, were tested against pancreatic α-amylase and intestinal α-glucosidase. These enzymes catalyse the hydrolysis of dietary oligo- and polysaccharides into monosaccharides and, consequently, are responsible for postprandial hyperglycaemia; therefore, their inhibition is one of the possible strategies to control glycaemic levels in diabetes mellitus. In addition, we investigated the aggregation tendency of the tested compounds, through direct and indirect methods, in order to evaluate the mechanism of their multiple action and discover if aggregation may contribute to the inhibition of the target enzymes. Overall, compounds 1, 3 and 4 exhibited the most favourable profile since they were shown to act as multi-target inhibitors of enzymes involved in pathways related to diabetes mellitus, without producing aggregates even at high micromolar concentrations and, therefore, can be promising agents for further developments.