Research On Design,Synthesis And Structure-activity Relationship Of Aldose Reductase Inhibitors Based On Quinoxalinone

Diabetes mellitus is a type of metabolic disorder of the body,seriously affecting human health and life,with high blood sugar as the main sign.Long-term high blood sugar in the human body,inevitably induce a variety of chronic complications,such as:retinopathy,peripheral neuropathy,renal microvascular disease,these complications are the biggest threat to diabetic patients.Studies have shown that complications of diabetes and glucose metabolism in the polyol pathway is closely related to metabolic abnormalities in the pathophysiology of diabetes mellitus metabolic abnormalities,aldose reductase inhibitor can effectively inhibit the excessive synthesis of sorbitol,and indirectly inhibit oxidative stress,is expected to develop into a drug which can prevent and treat of diabetic complications.This paper comprehensively analyzed the structures of the existing aldose reductase inhibitors and and chemical properties of the quinoxaline compounds,at the same time,the molecular docking software（Flex X Docking）was used to simulate the effect of quinoxalinone derivatives to demonstrate the rationality of the design which improve aldose reductase inhibitory activity by extending the carbon chain.Choosing 3-chloro-quinoxalin-2（1H）-one as the core structure,maintaining the N1 position as the hydrogen bond donor-acceptor carboxylic acid structure,Focus on modifying the length of the linker between the C3 and C3 side chains of the mother nucleus.The side chain aryl and quinoxalin bridging groups can be divided into four categories:the first is the C3-position aryl side chain directly connected with the mother nucleus;the second is C3-position aryl side chain through the ene;the third type is that the aryl side chain of C3 is connected to the mother nucleus via alkyl group and the fourth type is the introduction of methoxy or phenolic hydroxyl group on the side chain aromatic ring.13 carboxylic acid derivatives with side chains of different lengths were synthesized,and the structure-activity relationship between carbon chain length and aldose reductase inhibitory activity was further studied.The synthesized derivatives were tested for bioactivity in vitro by enzymatic kinetic method to characterize their enzyme inhibitory activity.The test results show that most of the target compounds have significant aldose reductase inhibitory activity in which 2-（3-（4-Hydroxyphenylpropenyl）-2-oxoquinoxalin-1（2H）-alkyl）acetic acid（Compound 20d）had the best inhibitory activity with an IC₅₀value of 93 n M,which was comparable to that of Epalrestat.Meanwhile,the in vitro activity showed a gradual increase with the extension of carbon chain.The structure-activity relationship analysis showed that extending the length of the linker between the C3 position of the quinuclidone nucleus and the C3 side chain significantly increased the aldose reductase inhibitory activity of the target compounds,while the introduction of phenolic hydroxyl group of the C3 side chain as well as C3 alkenyl bridging groups,also contribute to the aldose reductase inhibitory activity of the compounds.