Benzoxazoles Derived from Eugenol as Potential Agents against Arboviruses: Synthesis, Antiviral Studies, and Mechanistic Insights.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-12 DOI:10.1002/cmdc.202500323
Vinícius Augusto Campos Péret, Adriana Cotta Cardoso Reis, Lívia da Cunha Agostini, Isadora Oliveira Ansaloni Pereira, Glenda Nicioli da Silva, Diogo Teixeira Carvalho, Stefânia Neiva Lavorato, Saulo Fehelberg Pinto Braga, Geraldo Célio Brandão, Thiago Belarmino de Souza
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Abstract

The synthesis of new eugenol-benzoxazole derivatives and their antiviral evaluation against Orthoflavivirus zikaense (ZIKV), Alphavirus chikungunya (CHIKV), and Alphavirus mayaro (MAYV) are reported. Derivative 16 shows the highest potency and selectivity indices: 25 for ZIKV (EC50: 6.1 µM), 11 for CHIKV (EC50: 14.2 µM), and 24 for MAYV (EC50: 6.3 µM), 68 times more potent than ribavirin and amantadine drugs. RT-qPCR showed that benzoxazole 16 reduced the viral load of CHIKV after 24 and 48 h and of ZIKV after 24 h, demonstrating that it may be a promising antiviral agent. In cytopathic effect assays, benzoxazoles 16 and 23 showed cell monolayer protection against ZIKV and compounds 16 and 24 against CHIKV. None of these compounds showed virucidal activity, suggesting they act post-viral entry, targeting proteins related to viral replication rather than inactivating the virus before cellular infection. Molecular dynamics and MM/GBSA binding energy analysis of compound 16 on viral replication targets identified the capsid protein and nsP3 as the most promising targets, with binding free energies of -31.21 and -29.55 kcal/mol, respectively. The ligand remained deeply buried and well-confined in both binding sites, with minimal positional drift and a marked reduction in solvent-accessible surface area.

从丁香酚中提取的苯并恶唑作为虫媒病毒的潜在药物:合成、抗病毒研究和机制见解。
本文报道了新的丁香酚-苯并恶唑衍生物的合成及其对寨卡正黄病毒(ZIKV)、基孔肯雅甲病毒(CHIKV)和马亚罗甲病毒(MAYV)的抗病毒评价。衍生物16的效价和选择性指数最高:ZIKV效价为25 (EC50: 6.1µM), CHIKV为11 (EC50: 14.2µM), MAYV为24 (EC50: 6.3µM),效价是利巴韦林和金刚烷胺类药物的68倍。RT-qPCR结果显示,苯并恶唑16在24 h和48 h以及24 h后均能降低CHIKV病毒载量,表明其可能是一种有前景的抗病毒药物。在细胞病变实验中,苯并恶唑16和23对ZIKV具有细胞单层保护作用,化合物16和24对CHIKV具有细胞单层保护作用。这些化合物都没有显示出杀病毒活性,这表明它们在病毒进入后起作用,靶向与病毒复制相关的蛋白质,而不是在细胞感染之前使病毒失活。通过分子动力学和MM/GBSA结合能分析,化合物16在病毒复制靶点上的结合自由能分别为-31.21 kcal/mol和-29.55 kcal/mol的衣壳蛋白和nsP3是最有希望的靶点。配体在两个结合位点保持深埋和良好的限制,具有最小的位置漂移和溶剂可及表面积的显着减少。
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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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