Post-anaesthetic pulmonary oedema following upper airway obstruction.

Type 2 diabetes, driven by insulin resistance and β-cell dysfunction, is treated with drugs (metformin, GLP-1RAs, SGLT2 inhibitors, insulin) that lower glucose but often cause weight gain or hypoglycemia without restoring insulin sensitivity. Targeting protein tyrosine phosphatase (PTP1B), a key negative regulator of insulin signaling, represents a promising strategy for enhancing insulin sensitivity. A novel series of 2-(heteroarylthio)acetamido-1H-benzo[d]imidazole derivatives (PD22-01-PD22-11) was synthesized and evaluated for their inhibitory activity against PTP1B. The compounds were characterized and screened using a p-nitrophenyl phosphate (pNPP)-based enzymatic assay to determine their IC50 values. The in vitro evaluation revealed that several compounds, especially benzoxazole derivatives, exhibited moderate to potent PTP1B inhibition. Notably, compound PD22-10 ((5-nitrobenzo[d]oxazol-2-yl)thio linked) exhibited the highest potency (IC50 = 5.5 ± 1.1 µM), followed by PD22-08 ((6-chlorobenzo[d]oxazol-2-yl)thio linked, IC50 = 21.7 ± 1.6 µM), both showing markedly improved activity compared to the reference molecule (IC50 = 307.6 ± 28.4 µM). Molecular docking studies also showed that PD22-10 binds well to the catalytic pocket, with the highest docking score (82.9) of all the compounds tested. Molecular dynamics simulations (200 ns) confirmed the stability of the complex, with PD22-10 exhibiting a consistent conformation (average RMSD ≈ 1.4 Å) and indicating the most favourable binding free energy (ΔG binding = - 28.7 ± 0.3 kcal/mol), alongside the highest ligand burial (77.7%) relative to other analogues. Energy decomposition and interaction profiling identified Arg24, Tyr46, Val49, Phe182, Arg221, Gly259, and Gln262 as key contributors to the observed differences. In HEK293 cells, PD22-10 produced a concentration-dependent increase in STAT3 Tyr705 phosphorylation while leaving total STAT3 and PTP1B protein levels unchanged. This demonstrates effective cellular target engagement of PTP1B and positions PD22-10 as a compelling lead for further optimization toward interventions for type 2 diabetes and related metabolic disorders.