| Diabetes mellitus(DM),which is the third most lethal disease after cancer and cardiovascular disease,is a metabolic disease characterized by chronic hyperglycemia caused by multiple factors.Persistent hyperglycemia will inevitably lead to a series of serious diabetic complications,such as diabetic foot disease,ophthalmopathy and neuropathy,etc,which are the main cause of death and disability to diabetic patients.Current prevention and treatment strategies for diabetes overemphasize the control of blood glucose and other indicators,while little research conducted on diabetic complications.At present,there is only one clinical drug for diabetic complications,Epastat,which is only effective for diabetic neurological dysfunction.Therefore,it is of great social and scientific significance to develop effective drugs for the prevention and treatment of diabetic complications and fill the gaps in this class of drugs.The abnormal enhancement of glucose polyol pathway metabolism leads to the accumulation of sorbitol in the lesion tissue,which is the main pathogenesis of diabetic complications and the most important intervention target for its prevention and treatment.Aldose Reductase(AKR1B1)is the key rate-limiting enzyme in the polyol metabolic pathway.Designing synthetic aldose reductase inhibitors to inhibit aldose reductase activity and thus regulate abnormal activation of the glucose polyol metabolic pathway is a major way to create drugs against diabetic complications.At present,numerous aldose reductase inhibitors with different structures have been discovered,but all of them have failed to develop into effective therapeutic drugs for diabetic complications due to toxic side effects and metabolic instability,etc.Improving the molecular safety of inhibitors is a key issue that needs to be urgently addressed in the current anti-diabetic complication drug discovery.In this thesis,we designed and synthesized some novel aldose reductase inhibitors based on quinazolinone scaffold and determined the selectivity of aldose reductase inhibition by measuring the homologous enzymes of aldose reductase to obtain novel aldose reductase inhibitors with efficient AKR1B1 inhibition activity and high selectivity,and to advance the research process of drugs for the prevention and treatment of diabetic complications.In this thesis,firstly,4-quinazolinone was used as the scaffold,and the ester group and the benzyl group containing different substituents were introduced at the N-3 and N-1 positions,respectively,and further hydrolyzed to obtain quinazolinone acetate derivatives 5a-g;then 2-quinoxalinone was used as the scaffold,and the ester group was introduced at the N1 position and the benzyl group containing different substituents was introduced at the N4 position,and hydrolyzed to obtain a series of quinoxalinone acetate derivatives 10a-g Finally,3,4-dihydroquinolin-2(1H)-one was used as the scaffold,an ester group was introduced at the N1 position,a nitro group was introduced at the C6 position and reduced to an amine group,and further reaction with benzoyl chloride gave amides,and hydrolysis gave the quinoxalinone series of acetate derivatives 17a-g and 18a-c.The in vitro activities of aldose reductase and aldehyde reductase were tested on 4-quinazolinone and 2-quinoxalinone acetate derivatives 5a-g and 10a-g.The results showed that the halogen atom substitution on the benzyl side chain of the quinazolinone or quinoxalinone scaffold significantly improved the aldose reductase inhibitory activity and selectivity,with compounds 5g and 10 g containing 2-fluoro-4-bromo substitution having the best inhibitory activity and selectivity in their respective series.Analysis of the activity of the acetate derivatives 17a-g and 18a-c obtained with 3,4-dihydroquinolin-2(1H)-one as the parent nucleus reveals that the substitution of halogen atoms,methoxy and phenolic hydroxyl groups on the aryl group of C7 can have an enhancing effect on the activity,with the phenolic hydroxyl group being the most effective.Finally,molecular docking simulations were performed for the most active compounds 5g and 18 b among all compounds,and the results showed that the carboxyl groups,aryl side chains and the scaffold in the structures of compounds 5g and 18 b interacted well with the corresponding aldose reductase pockets,giving a mechanistic explanation for the conformational relationships of the above compounds at the molecular level and providing a theoretical basis for further structural design of aldose reductase inhibitors. |
