Filho José L Pereira, Pereira Renato B, Vieira Tatiana F, Sousa Sérgio F, Coelho José R A, Pinto Nuno F S, Coelho Catarina M M, Fernandes Maria José G, Castanheira Elisabete M S, Gonçalves Maria S T, Pereira David M
REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, Porto, Portugal.
LAQV/REQUIMTE, BioSIM - Department of Medicine, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, Portugal.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2535586. doi: 10.1080/14756366.2025.2535586. Epub 2025 Aug 21.
Eugenol (4-allyl-2-methoxyphenol), is the major chemical constituent in the essential oil of numerous plant species. Several biological properties have been described for this molecule, including modulation of enzymatic targets relevant for the inflammatory response, such as 5-lipoxygenase (5-LOX). As so, there is interest in expanding the chemical space of this molecule to develop new molecules to be used in inflammatory conditions. We describe the chemometric analysis of several eugenol derivatives, which show that the chemical space of the parent molecule was successfully expanded. All molecules were evaluated for their inhibition towards 5-LOX, an important player in inflammatory pathways. Four derivatives exhibited significant 5-LOX inhibitory activity, which prompted further studies. The most promising compounds, 4-allylbenzene-1,2-diol , ethyl-4-(4-allyl-2-methoxyphenoxy)butanoate , 3-(2-methoxy-4-(oxiran-2-ylmethyl)phenoxy)propyl acetate and 4-(3-(-butoxy)-2-hydroxypropyl)-2-methoxyphenol , were submitted to assays to validate their affinity and stability towards 5-LOX, which helped clarify the mechanism by which these molecules interact and inhibit this enzyme.
丁香酚（4-烯丙基-2-甲氧基苯酚）是众多植物物种精油中的主要化学成分。该分子具有多种生物学特性，包括对与炎症反应相关的酶靶点（如5-脂氧合酶（5-LOX））的调节作用。因此，人们有兴趣扩展该分子的化学空间，以开发用于炎症性疾病的新分子。我们描述了几种丁香酚衍生物的化学计量学分析，结果表明母体分子的化学空间得到了成功扩展。所有分子都被评估了对5-LOX的抑制作用，5-LOX是炎症途径中的一个重要参与者。四种衍生物表现出显著的5-LOX抑制活性，这促使了进一步的研究。最有前景的化合物，4-烯丙基苯-1,2-二醇、4-(4-烯丙基-2-甲氧基苯氧基)丁酸乙酯、3-(2-甲氧基-4-(环氧乙烷-2-基甲基)苯氧基)丙基乙酸酯和4-(3-(叔丁氧基)-2-羟丙基)-2-甲氧基苯酚，进行了实验以验证它们对5-LOX的亲和力和稳定性，这有助于阐明这些分子与该酶相互作用并抑制该酶的机制。
