The Design And Synthesis Of Aldose Reductase Inhibitors Based On Quinoline

Diabetes mellitus is a metabolic disorder due to chronic or relative insufficiency of insulin, in which the body’s ability to regulate blood glucose levels is disturbed, and it clinically characterized by hyperglycemia. Currently, the number of diabetes patients around the world increases every year, and it has become a worldwide problem. Clinical studies have evidence to prove that if human body in high glucose level for a long-term, it can induce a variety of chronic complications, these complications include three categories: retinopathy, peripheral neuropathy, kidney disease and so on. For treating diabetes and its complications, the patients need to invest a lot of resources for treatment every year. From the experiments and clinical studies in animals, it can be found that complications of diabetes are closely related with the glucose metabolism abnormally in the polyol pathway. The aldose reductase as a key rate-limiting enzyme in the polyol metabolic pathway, so that it played a crucial role in the pathogenesis of diabetic complications. Thus, inventing novel and effective aldose reductase inhibitors will bring the Gospel to people who have diabetes.Our research team has designed and synthesized aldose reductase inhibitors for years, a large number of drug molecules with high inhibit activity have been studied. They are the carboxylic acid inhibitor, whose vivo activity is not so good due to the pH of humans’ body. So the main purpose of this paper is to find some hydrophilic functional groups which can replace carboxyl.Research shows that compounds containing a quinoline ring have a variety of potent biological activity. Such as anti-cancer, anti-TB, anti-bacterial, anti-convulsants, antiinflammatory, treatment of cardiovascular disease and so on. So quinoline is a good drug molecule template in the biomedical field. In this work, the quinoline core structure is modified with a hydrophobic group and a hydrophilic group on its C-2 and C-4 position. Phosphoric acid and 2-thioxo-4-thiazolidinone quinoline derivatives were designed and synthesized, which have been tested for studying their activity-structure analysis.After testing the biological activity, we found that most compounds have high inhibitory activity. Therefore, quinoline structure can be applied to design and synthesis of aldose reductase inhibition, and it also broadens the application of quinoline in drug design. Wherein, phosphoric acids quinoline derivatives have poor inhibitory activity compared to carboxylic acids inhibitors, which illustrates that the phosphoric acid group is not a very effective hydrophilic group. In addition, 2-thioxo-4-thiazolidinone quinoline derivatives have high inhibitory activity. Of these derivatives, {5- [2-(4-bromo-2-fluorobenzyl) quinoline)] methylene-4-oxo-2-thioxo-thiazolidin-3-yl} acetic acid is the most active compound, with IC50 value of 10.8 nM, much more potent than Epalrestat(IC50=85.7 nM). The hydrophobic group of C-2 position can improve inhibitory activity of the compounds and the 2-thioxo-4-thiazolidinone was modified with a carboxylic acid can further improve inhibitory activity of the compounds, which provides a theoretical basis for the synthesis of inhibitors with higher activity. 5- [2-(4-bromo-2-fluorobenzyl) quinoline] methylene-2-thioxo-4-thiazolidinone has good inhibitory activity with IC50 value of 1.07μM. But it does not contain a carboxylic acid group, which can be a potential non-carboxylic acid aldose reductase inhibitory.