Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity

Forty-one
1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione
derivatives (MY1–41) were designed and synthesized
as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity
against diabetes mellitus (DM). All synthesized compounds (MY1–41) presented potential PTP1B inhibitory activities, with half-maximal
inhibitory concentration (IC50) values ranging from 0.41
± 0.05 to 4.68 ± 0.61 μM, compared with that of the
positive control lithocholic acid (IC50 = 9.62 ± 0.14
μM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 μM), was a reversible, noncompetitive inhibitor
of PTP1B. Circular dichroism spectroscopy and molecular docking were
employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate
palmitic acid (PA)-induced insulin resistance by upregulating the
expression of phosphorylated insulin receptor substrate and protein
kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose
tolerance and dyslipidemia in mice suffering from DM.