Synthesis, biological evaluation and molecular dynamics simulations of new sulfonylurea derivatives bearing biphenyl moieties as potential NLRP3 inhibitors

IF 2.8 3区化学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Research on Chemical Intermediates Pub Date : 2024-10-29 DOI:10.1007/s11164-024-05431-1

Xin Xiong, Ruifeng Zhang, Zhijian Min, Jinglong Liu, Peng Zheng, Xunping Li, Zhenli Min

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Abstract

Here in this work we designed and synthesized a series of new sulfonylurea derivatives bearing biphenyl moieties whose structures were confirmed by ¹H-NMR, ¹³C-NMR, IR and MS. The cytotoxicity of these compounds was first evaluated by MTT assay in J774A.1 cells and then their inhibitory activities against NLRP3 activation were evaluated in vitro in both J774A.1 and RAW264.7 cell lines initiated by LPS and ATP. The results showed that compound 10n (Sodium{(2-(nathphalen-2-yl) phenyl) carbamoyl} ((4-(2-hydroxypropan- 2-yl) furan-2-yl) sulfonyl) amide) had a good in vitro safety profile and a significant inhibitory effect on NLRP3 activation with an IC₅₀ value of 100.7 nM in RAW264.7 cells, which was only slightly weaker than MCC950 with an IC₅₀ value of 49.24 nM. Further computational studies (molecular docking, RMSD, RMSF, binding energy and DCCM analysis) indicated that 10n could be accommodated in the binding site of NLRP3 and strongly interact with NLRP3. Compound 10n has the potential to be further developed as a promising NLRP3 inhibitor.

Graphical abstract

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作为潜在 NLRP3 抑制剂的含有联苯分子的新型磺酰脲衍生物的合成、生物学评价和分子动力学模拟

在这项工作中，我们设计并合成了一系列含有联苯分子的磺酰脲类新衍生物，并通过 1H-NMR、13C-NMR、IR 和 MS 确认了它们的结构。首先用 MTT 法评估了这些化合物在 J774A.1 细胞中的细胞毒性，然后在体外评估了它们在 LPS 和 ATP 诱导的 J774A.1 和 RAW264.7 细胞系中对 NLRP3 激活的抑制活性。结果表明，化合物 10n（Sodium{(2-(nathphalen-2-yl) phenyl) carbamoyl} ((4-(2-hydroxypropan- 2-yl) furan-2-yl) sulfonyl) amide）具有良好的体外安全性，对 RAW264.7 细胞中的 NLRP3 激活具有显著的抑制作用，IC50 值为 100.7 nM，仅略低于 MCC950 的 IC50 值 49.24 nM。进一步的计算研究（分子对接、RMSD、RMSF、结合能和 DCCM 分析）表明，10n 可被容纳在 NLRP3 的结合位点上，并与 NLRP3 产生强烈的相互作用。化合物 10n 有潜力被进一步开发为一种有前途的 NLRP3 抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Research on Chemical Intermediates 化学-化学综合

CiteScore

5.70

自引率

18.20%

发文量

229

审稿时长

2.6 months

期刊介绍： Research on Chemical Intermediates publishes current research articles and concise dynamic reviews on the properties, structures and reactivities of intermediate species in all the various domains of chemistry. The journal also contains articles in related disciplines such as spectroscopy, molecular biology and biochemistry, atmospheric and environmental sciences, catalysis, photochemistry and photophysics. In addition, special issues dedicated to specific topics in the field are regularly published.