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.

中文翻译：

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含有 1,3,4-噻二唑基的噻唑烷-2,4-二酮衍生物作为具有抗糖尿病活性的新型 PTP1B 抑制剂的鉴定


设计并合成了 41 种含有 1,3,4-噻二唑基的噻唑烷-2,4-二酮衍生物 (MY1–41)，作为具有抗糖尿病 (DM) 活性的蛋白酪氨酸磷酸酶 1B (PTP1B) 抑制剂。所有合成的化合物（MY1-41）均表现出潜在的 PTP1B 抑制活性，与阳性对照石胆酸相比，半数最大抑制浓度（IC ₅₀ ）值范围为 0.41 ± 0.05 至 4.68 ± 0.61 μM酸（IC ₅₀ = 9.62 ± 0.14 μM）。最有效的化合物 MY17 (IC ₅₀ = 0.41 ± 0.05 μM) 是 PTP1B 的可逆、非竞争性抑制剂。采用圆二色光谱和分子对接分析MY17和PTP1B之间的结合相互作用。在HepG2细胞中，MY17治疗可以通过上调磷酸化胰岛素受体底物和蛋白激酶B的表达来减轻棕榈酸（PA）诱导的胰岛素抵抗。在体内，口服MY17可以降低空腹血糖水平，改善糖耐量和血糖水平。患有糖尿病的小鼠的血脂异常。