Design, synthesis and biological activity of novel sulfonatocalix[4]arene-based organophosphorus toxicant scavengers

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-10-01 DOI:10.1016/j.bioorg.2025.109067

Han Zhang , Litian Jia , Zhenhai Hu , Genping Xue , Sidan Sun , Jixin Ma , Yang Liu , Qingbin Meng

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引用次数: 0

Abstract

Chemical scavengers based on macrocyclic compounds have made remarkable progress in combating organophosphate toxicants. However, their structural diversity, structure-activity relationships and in vivo therapeutic effects still need further clarification. Here, 9 sulfonatocalix[4]arene derivatives were designed, synthesized and biologically evaluated using in vitro enzymatic assays. Through systematic structure-activity relationships optimization, compounds 1b, 1f and 1g exhibited particularly remarkable scavenging activities against organophosphate toxicants, with detoxification half-lives of 2.9 min, 4.6 min and 4.1 min, respectively. In vitro studies revealed their cytoprotective effects via reducing intracellular reactive oxygen species, alleviating lipid peroxidation and inhibiting proinflammatory cytokine release. In organophosphate-intoxicated mouse models, these compounds improved survival rates, mitigated seizure severity and reduced multi-organ injury. Notably, compound 1f stood out with the most outstanding performance, emerging as a promising lead compound for the development of novel therapies against organophosphate poisoning.

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新型磺胺基芳烃类有机磷毒物清除剂的设计、合成及生物活性研究

基于大环化合物的化学清除剂在对抗有机磷毒物方面取得了显著进展。但其结构多样性、构效关系及体内治疗效果等仍需进一步研究。本研究设计、合成了9个磺原基[4]芳烃衍生物，并用体外酶法对其进行了生物学评价。通过系统构效关系优化，化合物1b、1f和1g对有机磷毒物的清除活性特别显著，其解毒半衰期分别为2.9 min、4.6 min和4.1 min。体外研究显示其细胞保护作用通过减少细胞内活性氧，减轻脂质过氧化和抑制促炎细胞因子的释放。在有机磷中毒小鼠模型中，这些化合物提高了存活率，减轻了癫痫发作的严重程度，减少了多器官损伤。值得注意的是，化合物1f表现最为突出，有望成为开发抗有机磷中毒新疗法的先导化合物。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.