The Research Of Aldose Reductasinhitors Based On The Structure Of Pyridine Quinoxalon

Diabetes mellitus is a kind of common epidemic disease.It is widely distributed.With the improvement of people's living standard,the incidence of diabetes is increasing year by year.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,nervous system disease,arteriosclerosis,renal disease,cardiovascular disease and stroke.At present,the pathogenesis of diabetic complications is still under study.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.The purpose of this article is based on the design and synthesis of pyridine quinoxalinone structure of multifunctional aldose reductase inhibitors,and make it as efficient treatment of the complications of diabetes mellitus of great potential for drug.this article is based on the Pyridine as nucleus quinoxalone,we can modify side chain of C3-N1.Specifically,The activity of N-1 is further enhanced by the introduction of carboxyl group and the C-3 position of the larger volume side chain to the hydroxyl group.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,the synthetic compounds were analyzed and demonstrated by molecular simulation.We have synthesized chemical compound 52,the most efficient potential drug,which has aldose reductase restrain rate IC50 of 26.9nM.It shows excellent antioxidantactivityand eliminate ratios are 97.3%?78.8%?49.6% under DPPH of 100?M?50?M?10?M,respectively,Through Leptin gene knockout bioexperiment on db/db mouse,parameters including GTT,8-different prostaglandins and so on.Which indicates Compound 52 not only reduce blood glucose,but also has some antioxidant effect.