Research On Design,synthesis And Activity Of A Multifunctional Aldose Reductase Inhibitor

Diabetes is a metabolic disorder syndrome which is characterized by hyperglycemia.In the persistent state of hyperglycemia,the body will inevitably induce a variety of complications such as cataracts,retinopathy,peripheral neuropathy.Those complications often have a great threat to human health.Evidence shows that the abnormal metabolism of glucose in the polyol pathway and the accumulation of sorbitol are significantly associated with the onset of diabetic complications.As a key rate-limiting enzyme in the polyol pathway,aldose reductase plays a crucial role in catalyzing the conversion of glucose to sorbitol.Aldose reductase inhibitors can effectively inhibit the accumulation of sorbitol,thereby indirectly inhibiting the body’s oxidative stress.Therefore,the purpose of this study is to design and synthesize a multifunctional aldose reductase inhibitor with both aldose reductase inhibitory activity and antioxidant activity.In this paper,the mechanism of inhibitory activity of aldose reductase was simulated at the molecular level by using the software of Docking,and its design rationality was demonstrated by the specific combination of target molecule and aldose reductase.On this basis,the quinoxaline nucleus was used as the structure,the side chain was modified at the C3-N1 position.The carboxyl group was introduced at the N1 position.The Heck reaction was used to introduce the styryl side chain containing the phenolic hydroxyl group at the C3 position.The target product was tested in vitro for its inhibition activity and selectivity.Through experiments,the IC₅₀was 17.9 n M,which showed that it had high inhibition efficiency.The aldehyde reductase inhibition rate was 34.96%with the compound at10^-5M,which showed high selectivity.In addition,compound 9 also showed better activity in anti-oxidation.Also,DPPH radical scavenging rates were 96.7%,80.8%and 59.5%respectively at 100μM,50μM and 10μM.Then,the target product was tested in vivo to determine the therapeutic effect by using the streptozotocin（STZ）-induced diabetic mice.After given medicine for 21days,the mice were tested to show its efficacy.The values of MDA of the mice given the target compound at the dose of 100 mg/kg and 200 mg/kg were both lower than the control group.And the values were significantly different（p<0.05）,which indicated that the target compound can inhibit oxidative stress effectively and improve the antioxidant level of body.But compared to the control group,the target compound had no significant effect on the regulation of blood glucose in diabetic mice by testing glucose（GLU）,glucose tolerance（GTT）.