Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kgp.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 +/- 1.35 compared to the standard Pioglitazone (150.2 +/- 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The his-topathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione de-rivatives represent novel anti-diabetic agents with least side effects.

Automated summary

Despite advancements in Diabetes mellitus management, designing and synthesizing drug molecules that effectively improve hyperglycemia and associated complications in diabetic patients remains challenging. In this study, pyrimidine-thiazolidinedione derivatives were synthesized, characterized, and evaluated for their anti-diabetic properties. The synthesized compounds were analyzed using various techniques, including NMR, FTIR, and Mass Spectrometry. In-silico ADME studies confirmed the compounds met Lipinski's rule of five. In-vivo evaluation in diabetic rats showed that compounds 6e and 6m significantly reduced blood glucose levels without causing weight gain. Biochemical and histopathological analyses further supported the anti-diabetic effects of these compounds. Based on these findings, pyrimidine-based thiazolidinedione derivatives could be considered as novel anti-diabetic agents with minimal side effects.