Thiazolidinediones (TZDs) are one of the important clinically established antidiabetic agents. Amino-acid and peptides have an advantage of better target selectivity and specificity. As hybrids, they also improved absorption and showed better bioavailability, which in turn makes them safer. Hence, here an effort has been made to synthesize hybrids of thiazolidinedione with amino-acids and peptides and evaluate their antidiabetic and cardioprotective effect in streptozotocin-nicotinamide (STZ-NA) induced Type 2 diabetes mellitus (T2DM) rat models.

A series of 14 thiazolidinedione-5-acetic acid hybrids with of different amino-acids and peptide combinations were synthesized, characterized and further screened for antidiabetic and cardioprotective activity.

Among all, six compounds T1 (SSDMA1), T4 (SSDMA4), T5 (SSDMA5), T7 (SDMA13), T9 (SSDMA15) and T13 (SSDMA49) showed better antioxidant activity and comparable % glucose uptake by yeast cells.

Hence, the in vivo antidiabetic screening was done for these six compounds. Among all six T1, T7, T13 showed significant blood glucose level decrease compared to standard pioglitazone HCl. Also T1, T7 and T13 showed better antioxidant activity with lower IC₅₀ value than standard ascorbic acid, and hence in vivo cardioprotective studies were done for these. The ECG studies showed that T1 (SSDMA1) and T7 (SSDMA13) were better effective than SDMA49 (T13) in restoring the normal functioning of the heart, thus may help in preventing the development of diabetic cardiomyopathy (DCM) and controlling T2DM.