Design And Synthesis Of Phenol Hydroxyl-containing Benzothiadiazine And Pyriddiazine Derivatives And Study On Their Biological Activities

Diabetes mellitus as a complex metabolic disorder is a chronic disease requiring long-term medical care.Diabetic patients suffer from the complications including retinopathy,nephropathy,neuropathy and cataracts.Evidence shows the development and progression of the complications are related to the activation of aldose reductase(ALR2,EC 1.1.1.21),a speed-limited enzyme in the polyol pathway.Thus,ALR2 inhibition has received considerable attention over decades as an attractive and a promising therapeutic strategy.Diabetes is a state of increased oxidant stress and accumulating evidence reveal that oxidative damage may play a role in the pathogenesis of diabetes mellitus and its complications.Therefore,synthesis of aldose reductase inhibitors(ARIs)possessing antioxidant activity seems to be desirable.First,we prepared three benzothiadiazine 1,1-dioxide derivatives and three3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide derivatives,which are the best ARIs according to our previous work,and comparably study on their antioxidant activity in vivo and in vitro.Results showed the benzothiadiazine1,1-dioxide derivatives have higher antioxidant activity than3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide derivatives.In order to improve the antioxidant activity of the ARIs,We synthesized a series of 3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide derivatives bearing different substituent groups at the C7 positions and a N2-benzyl group with hydroxyl groups at different position of the benzyl ring based on the previous work in our lab.Then we evaluated their activity against ALR2 and their antioxidant activity.All of the derivatives bearing a N2-benzyl group with hydroxyl groups at the benzyl ring showed stronger antioxidant activity than their correspond derivatives.Continue investigations on ARIs exhibiting better antioxidant activity were carried out with benzothiadiazine 1,1-dioxide core structure.We synthesized benzothiadiazine 1,1-dioxide derivatives bearing different substituent groups at theN2-benzyl group with hydroxyl groups at different position of the benzyl ring.Both core structures based derivatives mentioned above feature phenol hydroxyl groups in N2-benzyl ring.The antioxidant activity of those derivatives were studied Further efforts to develop novel ARIs possessing antioxidant property resulted in novel 1,2-benzothiazine 1,1-dioxide derivatives bearing phenol hydroxyl group in C7 position of the core structure.The results from these studies have encouraged us to continue our investigations into the design of more potent analogues by conducting appropriate modifications based on the sulfonyl-containing scaffold.