Design, synthesis, characterization and antidiabetic evaluation of 3,5-substituted thiazolidinediones: Evidenced by network pharmacology, Molecular docking, dynamic simulation, in vitro and in vivo assessment

In search of new antidiabetic agents, heterocyclic compounds containing 3,5-Substituted thiazolidinedione moieties were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 3,5-Substituted thiazolidinedione ring-system (6a-6c). Comprehensive physicochemical and spectral analyses, including FTIR, HR-MS, 1 H NMR and 13 C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their In vivo anti-diabetic activity against diabetes induced wistar rats and In vitro activity against α-amylase, α-glucosidase and glucose uptake by yeast cells. On the basis of the combined results of network pharmacology , In vitro and animal study experiments revealed that the compounds 6c predicted to have the greatest effect out of the compounds (6a-6c), showing interactions with targets exhibited potential binding patterns against the active site of target α-amylase, α-glucosidase with modulating AMY2A, GAA, PPARG, PIK3CA, PRKCB, INSR, and PRKCB signalling pathways and this is evidenced by molecular docking, dynamics simulation (MD) studies. Further, compound 6c showed In vitro α-amylase, α-glucosidase inhibitory activity with IC 50 value of 86.06 ± 1.1 μM and 74.97 ± 1.23 μM as opposed to standard acarbose (IC 50 value of 26.89 ± 3.12 and 29.25 ± 0.15 μM) and 58.23 ± 0.13 % of glucose uptake and also exhibited significant reduction (p < 0.001) in blood glucose levels (114 ± 1.17 mg/dL) comparable to the effect of pioglitazone (102.2 ± 0.79 mg/dL). The present study suggests that modified thiazolidinediones act as potential lead compounds to carter the need of antidiabetic agents. • 3,5-Substituted Thiazolidinedione hybrids were synthesized. • Molecular dynamics simulation, Molecular docking and Network pharmacology studies were performed. • In-vitro α-amylase, α-glucosidase inhibitory assay was performed. • Compound 6c showed promising In-vitro α-amylase inhibitory activity. • Compound 6c exhibited anti-diabetic activity against diabetes induced wistar rats.