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

2024; American Chemical Society; Volume: 67; Issue: 10 Linguagem: Inglês

10.1021/acs.jmedchem.4c00676

1520-4804

Mengyue Li, Huiyun Li, Xiaofeng Min, Jinping Sun, Bingwen Liang, Lei Xu, Jia Li, Shao‐Hua Wang, Xue-Tao Xu,

Protein Kinase Regulation and GTPase Signaling

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.