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

Sixteen novel thiazolidinedione (TZD) and rhodanine (RD) derivatives were designed and synthesized by introducing a pyrimidine moiety at different sites of pioglitazone's structure. The effects of synthesized compounds on regulating glucose metabolism, improving insulin sensitivity, and activating the peroxisome proliferator-activated gamma receptor (PPAR-gamma) were evaluated in beta TC6 cells. Compounds TZDs # 7a, 7b, 7c, and 29 reduced the basal insulin secretion by similar to 20.0-67.0% and increased insulin secretion stimulated by glucose by similar to 25.0-50.0% compared to control. Compounds TZDs # 14 and 21 and RDs # 33a-b and 33d-f increased basal insulin secretion by similar to 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-gamma structure revealed exothermic binding modes through hydrogen bonding, van der Waals forces, and pi-pi 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-gamma relative to pioglitazone. They are recommended for further development as potential antidiabetic agents.