Novel Thiazolidinedione and Rhodanine Derivatives Regulate Glucose Metabolism, Improve Insulin Sensitivity, and Activate the Peroxisome Proliferator-Activated γ Receptor

increased basal insulin secretion by ∼20.0-100.0%, while its glucose-stimulated secretion remained unchanged. These findings suggested that the former compounds can act as antihypoglycemic during fasting and antihyperglycemic during postprandial conditions. The latter compounds should be administered before meals to avoid their hypoglycemic effect. Additionally, both TZDs and RDs improved insulin sensitivity by increasing glucose uptake by 17.0-155.0% relative to control. In silico molecular docking of synthesized drugs onto the PPAR-γ structure revealed exothermic binding modes through hydrogen bonding, van der Waals forces, and π-π stacking with binding affinities of -6.02 to -9.70 kcal/mol. Insights into the structure-activity relationship revealed that the introduction of pyrimidine linked to sulfonyl or peptide groups accounted for increased antidiabetic activity. These results demonstrated novel TZDs and RDs with high potency in stimulating insulin secretion, enhancing insulin sensitivity, and activating PPAR-γ relative to pioglitazone. They are recommended for further development as potential antidiabetic agents.