Synthesis and Antidiabetic Evaluation of Novel 2,4-Thiazolidinedione Derivatives Targeting Key Carbohydrate-Digesting Enzymes.

Diabetes mellitus is a long-term metabolic disease associated with elevated glucose levels in blood and still constitutes one of the major public health issues worldwide. Inhibition of carbohydrate-digesting enzymes like α-amylase and α-glucosidase has been found to be effective in controlling postprandial hyperglycemia. The current study focused on designing, synthesis, characterization, and evaluation of novel 2,4-thiazolidinedione derivatives (D1-D5) as potent antidiabetic drugs utilizing combined in silico, in vitro, and in vivo techniques. Results from drug-likeness and ADME analyses indicated that all synthesized derivatives met Lipinski's rule of five and had desirable pharmacokinetics properties along with reduced toxicity. Molecular docking against maltase-glucoamylase (human; PDB ID: 3TOP) protein showed good binding affinities of both D1 and D5 derivatives (-7.74 and -7.40 kcal/mol respectively) due to stable interactions with catalytic residues of enzymes. Inhibition of enzymes in vitro showed that D1 and D5 had the highest inhibitory activities of all synthesized derivatives, with IC50 of 33.86 ± 2.1 and 37.55 ± 1.7 μM against α-amylase and 29.81 ± 3.2 and 32.43 ± 1.2 μM against α-glucosidase, respectively. Cytocompatibility tests on L6 myoblast cells proved that the lead compounds were well tolerated. In addition, studies in a model of Drosophila melanogaster induced by a high-sugar diet revealed a significant decrease in the level of glucose concentration depending on the dose, especially for D1 and D5, indicating their antihyperglycemic activity in vivo. Thus, these data confirm that D1 and D5 can be regarded as promising lead compounds for the development of new antidiabetics acting via inhibition of carbohydrate-metabolizing enzymes.