舍曲林作为抗克氏锥虫药物开发的支架:新衍生物的设计和计算靶点筛选。

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-09 DOI:10.1002/cmdc.202500408
Ali S Mijoba, Zuleyma Blanco, Nereida J Parra-Giménez, Katiuska E Chávez, Alirica I Suárez, Esteban Fernandez-Moreira, Hegira Ramírez, Xenón A Serrano, Sandra Espinosa, Jaime E Charris
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引用次数: 0

摘要

由于药物再利用的优势,在已批准的药物基础上发现治疗恰加斯病的新化疗药物已成为确定新候选药物的一种策略。本研究报道了抗抑郁药物舍曲林对克氏锥虫无鞭毛体型的IC50值为7.8±1.7µM。通过形成第三酰胺对活性进行优化,得到了一个小的化合物库,其中两种化合物SMBT和SM04对寄生虫无尾线虫的体外活性比舍曲林提高了4.3倍和2.7倍,安全指数分别为>55.6和25.4。由于(O)CN键周围的旋转受阻,叔酰胺以E/Z旋转体的混合物存在,通常是不可分离的,它们在核磁共振光谱中显示单独的信号。E/Z转子的1H共振的微分分配是基于各向异性溶剂引起的位移效应的大小,并由二维核奥弗豪瑟效应谱证实。对命中化合物的计算分析表明,SMBT对三种靶标(半乳糖酰脲酶、二氢叶酸还原酶和角鲨烯合成酶)具有显著的亲和力,而SM04与一种靶标(角鲨烯合成酶)具有显著的相互作用。这些结果不仅提示了所研究化合物的作用机制,而且为合理设计具有潜在增强锥虫活性的新衍生物提供了有价值的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sertraline as a Scaffold for Antitrypanosoma Cruzi Drug Development: Design of Novel Derivatives and Computational Target Screening.

Due to the advantages of drug repurposing, the discovery of new chemotherapeutic agents for the treatment of Chagas disease based on approved drugs has become a strategy for identifying new candidates. In this work, the antidepressant drug sertraline is reported, with an IC50 of 7.8 ± 1.7 µM against the amastigote forms of Trypanosoma cruzi. The optimization of activity through the formation of tertiary amides results in a small library of compounds, where two compounds, SMBT and SM04, show increases of 4.3 and 2.7 times in vitro activity against the amastigote form of the parasite, and a safety index of >55.6 and 25.4, respectively, compared to sertraline. Due to hindered rotation around the (O)CN bond, the tertiary amides exist as a mixture of E/Z rotamers, typically inseparable, which display separate signals in their NMR spectra. The differential assignment of the 1H resonances of the E/Z rotamers is based on the magnitude of anisotropic solvent-induced shift effects and confirmed by 2D nuclear Overhauser effect spectroscopy. Computational analysis of the hit compounds reveals that SMBT showed significant affinity for three targets (galactopyranose mutase, dihydrofolate reductase, and squalene synthase), while SM04 displays notable interaction with one (squalene synthase). These results not only suggest a plausible mechanism of action for the studied compounds but also provide valuable insights for the rational design of new derivatives with potentially enhanced trypanocidal activity.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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