The Design And Synthesis Of Aldose Reductase Inhibitors Based On1,2-benzothiazine1,1-dioxide

According to the reports of the WHO, diabetes has become a common disease.Without timely diagnosis and proper treatment, the disease leads to a variety of chroniccomplications, such as cataracts, retinopathy and neuropathy. So the development ofeffective therapeutic drugs attracts more and more concern.A large number of clinical studies show that the tissue’s accumulation of sorbitol bypolyol pathway leads to diabetes complications, and aldose reductase (ALR2) is the keyrate-limiting enzyme. The aldose reductase inhibitors (ARIs) can effectively improve thediabetes polyol pathway abnormal so as to achieve effective drugs for the treatment ofdiabetic complications. The structure of1,2-benzothiazine1,1-dioxide is important inmedicinal chemistry, especially used as aldose reductase inhibitor.The carboxylic acid inhibitor presents as an important structure of aldose reductaseinhibitors, but its vivo activity is not so good due to the pH of humans’ body. The mainpurpose of this paper is to find some hydrophilic functional groups which can replacecarboxyl. A series of hydroxyl and nitro compounds were synthesized and their biologicalactivities were tested subsequencently, in order to obtain a series of potent ARIs.Based on the previous work, we prepared1,2-benzothiazine1,1-dioxide in an efficientway. Then we synthesized a series of hydroxyl and nitro compounds.When testing the biological activity, we found the biological activity of carboxylic1,2-benzothiazine1,1-dioxide derivatives were better than that of corresponding hydroxyl1,2-benzothiazine1,1-dioxide derivatives, and both kinds of the compounds performed notso good activities. It assumed that the common defect of these end-products was the chainlength was shorter in C4position. Because the nitro and hydroxyl group don’t put well intothe anion pocket when interact with the aldose reductase. If we screen the length of carbonchain in sequences then do hydroxylation or nitro reaction in order to extend the length ofchain in C4position, the biological activities of the series will be better.