Sulfonyl Group-Containing Compounds in the Design of Potential Drugs for the Treatment of Diabetes and Its Complications

Sulfonyl group-containing compounds constitute an important class of therapeutical agents in medicinal chemistry presumably because of the tense chemical structure and functionality of the sulfonyl, which could not only form hydrogen bonding interactions with active site residues of biological targets but also, as incorporated into core ring structure, constrain the side chains and allowed their specific conformations that fit the active sites. This review focuses on sulfonamides and sulfones, which cover more than 40 series and are associated with at least 10 potential pharmaceutical targets in pathways of glucose metabolism and insulin signaling. A large number of such compounds have been reported as pharmaceuticals every year in the last decade. In particular, increasing studies suggest that sulfonamides and sulfones play a key role in the design of pharmaceutical agents with potential application for the treatment of diabetes and its complications. First, they are inhibitors of a variety of enzymes including 11 beta-hydroxysteroid dehydrogenase type 1, alpha-glucosidase, carnitine palmitoyltransferase and cytosolic phosphoenolpyruvate carboxykinase, and in turn involved in the regulation of the metabolism of glucose. In addition, they are active as activators of glucokinase and as antagonists of ghrelin receptors. These enzyme and receptors are tightly associated with the regulation of glucose metabolism and the improvement of insulin resistance. Secondly, sulfonamides and sulfones act in the insulin secretion. As agonists, they activate insulin receptor tyrosine kinase and thus increase insulin sensitivity. Moreover, they as inhibitors suppress protein tyrosine phosphatase 1B and dipeptidyl peptidase IV, and thus normalize the insulin signaling pathway. Finally, a number of sulfonamides and sulfones are inhibitors of aldose reductase, which have been linked to diabetic complications.