The Research Of New Aldose Reductase Inhibitors Based On Quinoxaline-2(1H)-one As The Parent Structure

Diabetes mellitus(DM) is a metabolism disease that is characterized by hyperglycemia. It has threatened people’s daily life greatly as the increasing number of patients because of upturn of living standard. DM is a blood glucose metabolic disorder syndrome composed by pancreas recession, insufficient insulin for insulin resistance and decline of insulin activity. However, what threat people most is not DM itself but a series of complication such as cataract, retinopathy, neuropathy, nephropathy and atherosis. As a result, developing new drugs and treat method which can cure DM and its syndrome have become an urgent task. Experiment data indicates that aldose reductase can resist abnormal accumulation of sorbitol in polyol pathway and restrain oxidative stress level indirectly which is a good indicator of DM cure. But based on our research, this is not a comprehensive treatment. Only when controlling the amount of sorbitol and oxidative stress level at the same time can we get a satisfying result. This dissertation aims to find a derivative that unites reductase inhibition and inoxidizability.Based on quinoxaline-2(1H)-one as the parent structure, we can modify side chain of C3-N1. Specifically, graft styryl contains phenolic hydroxyl group on C3 and carboxyl on N1. And then test external biological activity to confirm its reductase inhibition and inoxidizability. Internal test was conducted on mice to prove the curative effect. Finally, simulate the cure mechanism on molecule level on Flex Docking platform.We have synthesized chemical compound 54, the most efficient potential drug, which has aldose reductase restrain rate IC50 of 18.2n M. It shows excellent antioxidant activity and eliminate ratios are 95.4%、78.8%、49.6% under DPPH of 100μ M、50μ M、10μ M respectively. Through Leptin gene knockout bioexperiment on db/db mouse, parameters including GTT, CAT, 8-different prostaglandins, TG and TC all indicate that chemical compound 54 can not only promote glucose absorption and adjust glucose level but also stimulate the secretion of insulin and reveal antioxidant to some extent.