Discovery of Thiopyrimidinone Derivatives as a New Class of Human Aldose Reductase Inhibitors

Diabetes is a chronic metabolic disorder characterized by insufficient insulin production, the cells’ inability to use this insulin, or a combination of both, leading to secondary complications such as diabetic neuropathy and retinopathy. One way to prevent or control such complications is the use of aldose reductase (AR) inhibitors. In this work, we synthesized and tested new candidates for human AR inhibition containing a 2-thiopyrimidin-4-one heterocycle as a central ring. The fifteen derivatives were tested in vitro and their binding modes were evaluated via molecular docking simulations. AR inhibition assays showed that all synthesized compounds were able to inhibit the AR enzyme at 50 μM. From these results, seven compounds were noteworthy and had their half maximal inhibitory concentration (IC50) values estimated, ranging from 2.0 to 14.5 μM. Molecular docking simulations showed that these compounds bind specifically to the catalytic subpocket and the results indicate a good association between in vitro and in silico studies.