Novel Indole Clubbed Thiazolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B)

Abstract

The escalating challenge in the carbohydrate metabolic disorders like diabetes mellitus in the modern era necessitates the development of antidiabetic agents that work on the unexplored pathways. In this study, the synthesis of a novel series of indole clubbed thiazolidinediones (TN01-TN08) for protein tyrosine phosphatase 1B (PTP1B) inhibition as insulin sensitizers for antidiabetic therapy is presented. The molecular hybridization approach was utilized to synthesize the analogues and FT-IR, ¹H NMR, ¹³C NMR and LC-MS were employed to determine the structures of the newly synthesized compounds. The interaction mechanisms with the receptor, binding free energy and amino acid residues of the receptor enzyme involved in the interactions with different analogs were evaluated using molecular docking. The cytotoxic effects of synthesized compounds were assessed by MTT assay on HepG2 cell lines. Based on the cytotoxic assay, compounds were further treated with rat L6 myotubes as a model system to investigate peripheral insulin resistance and uptake of glucose by the cells. Further, selected compounds were subjected to an in vitro PTP1B inhibitory assay and most potential PTP1B inhibition was demonstrated by analogues TN05 and TN04 (IC₅₀ 28.52 and 32.67 respectively), which could further develop as therapeutically significant antidiabetic candidates.