New Selective Inhibitors of α-Glucosidase for the Treatment of Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post-prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α-amylase and α-glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α-amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α-glucosidase with low micromolar IC₅₀ (3.64-7.98 μM) compared to the acarbose (IC₅₀ 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α-amylase (IC₅₀>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α-glucosidase, which support the existence of both active site and allosteric interactions.