Design and Synthesis of a Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt to Discover Novel Anti-diabetic Agents.,ChemMedChem

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Design and Synthesis of a Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt to Discover Novel Anti-diabetic Agents.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-05-10 , DOI: 10.1002/cmdc.202000055
Ashish D Patel _{1,

2} , Thopallada Y Pasha ₃ , Paras Lunagariya ₄ , Umang Shah ₁ , Tushar Bhambharoliya ₅ , Rati K P Tripathi _{2,

6}

Affiliation

Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin‐4‐one derivatives 8 –22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC₅₀ values in the micromolar range. 5‐(Furan‐2‐ylmethylene)‐2‐(4‐nitrophenylimino)thiazolidin‐4‐one (17 ) exhibited potency with a competitive type of enzyme inhibition. structure–activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group‐including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H‐bonding and π–π interactions were responsible for optimal binding and effective stabilization of virtual protein‐ligand complexes. Furthermore, in‐silico pharmacokinetic properties of test compounds predicted their drug‐like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.

中文翻译：

噻唑烷-4-酮衍生物作为蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂的库的设计与合成：尝试发现新型抗糖尿病药。

蛋白质酪氨酸磷酸酶1B（PTP1B）是治疗糖尿病的重要靶标。一系列噻唑烷-4-酮衍生物的8 - 22被设计，合成和研究作为PTP1B抑制剂。新分子以微摩尔范围的IC ₅₀值抑制了PTP1B 。5-（呋喃-2-基亚甲基）-2-（4-硝基苯基亚氨基）噻唑烷-1--4-（17）显示出具有竞争性酶抑制类型的功效。结构-活性关系研究揭示了对于这些类似物的效力重要的各种结构方面。研究结果表明抑制PTP1B需要使用含硝基的疏水性杂芳基环。分子对接研究与实验结果具有良好的相关性。H键和π-π相互作用是虚拟蛋白质-配体复合物的最佳结合和有效稳定的原因。此外，in-silico 受试化合物的药代动力学特性预测了其潜在的口服用途，可作为抗糖尿病药。此外，已提出了一个结合位点模型，该模型证明了影响抑制剂效能和结合亲和力的关键药效学特征，可用于设计未来的潜在药物。 PTP1B抑制剂。

更新日期：2020-07-03

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