Synthesis, Biological evaluation, and computational study of 2-((2-oxo-2-(arylamino)ethyl)thio)-1H-benzodimidazole-5-carboxylic acids as PTP1B inhibitors for the treatment of type 2 diabetes

Protein tyrosine phosphatase 1B (PTP1B) is a promising therapeutic target for the treatment of metabolic disorders, including type II diabetes mellitus (T2DM). In this study, a series of 2-((2-oxo-2-(arylamino)ethyl)thio)-1 H -benzodimidazole-5-carboxylic acid derivatives were synthesized and evaluated for their PTP1B inhibitory activity. Among the compounds tested for PTP1B inhibition, compound DK22-09, bearing a 4-bromo substitution, exhibited the highest inhibitory activity (IC 50 = 269.4 µM). Structure-activity relationship analysis indicated that halogen substitutions, specifically 4-bromo and 4-chloro groups, greatly enhanced PTP1B inhibitory potency, whereas methoxy and fluoro substitutions were less effective. We performed molecular docking and molecular dynamics (MD) simulations of potent compounds in this series. Docking studies using the GOLD software identified compound DK22-09 as the most promising candidate, with a ChemPLP docking score of 77.8 and an IC 50 of 269.4 µM. MD simulations confirmed the stability of the ligand-protein complexes, with Compound DK22-09 demonstrating favourable binding interactions at site C of PTP1B. MM/GBSA calculations further supported these findings, highlighting the significance of hydrophobic interactions in ligand binding. Overall, the study's findings establish compound DK22-09 as a promising lead candidate for PTP1B inhibitor development. Further structural optimizations and in-vivo studies are warranted to improve its potency and support the development of this novel class of PTP1B inhibitors as antidiabetic agents.