de Oliveira Mariana Belizário, Gazolla Poliana Aparecida Rodrigues, Meireles Leandra Martins, Teixeira Róbson Ricardo, Silva Danilo Aniceto da, Barbosa Luiz Claudio Almeida, Bezerra Morais Pedro Alves, Oliveira Osmair Vital de, Nascimento Claudia Jorge do, Andrade Barrela Pedro Henrique de, Junker Jochen, Dos Santos Nayara Araujo, Romão Wanderson, Lacerda Valdemar, Júnior Waldir Cintra de Jesus, Gomide Mizubuti Eduardo Seiti, de Queiroz Vagner Tebaldi, Profeti Demetrius, Moraes Willian Bucker, Scherer Rodrigo, Costa Adilson Vidal
Departamento de Química e Física, Grupo de Pesquisa de Estudos Aplicados em Produtos Naturais e Síntese Orgânica (GEAPS), Universidade Federal do Espírito Santo, Alto Universitário, s/n, 29500-000 Alegre, Espírito Santo State, Brazil.
Universidade de Vila Velha, Departamento de Farmácia, Programa de Pós-Graduação em Ciências Farmacêuticas, Av. Comissário José Dantas de Melo 21, 29102-770 Vila Velha, Espírito Santo State, Brazil.
J Agric Food Chem. 2025 Jun 11;73(23):14290-14299. doi: 10.1021/acs.jafc.4c12770. Epub 2025 Jun 3.
Azole-based fungicides are among the market's most widely used and effective agents. However, their indiscriminate use can lead to reduced efficacy and increased pathogen resistance. This highlights the need for novel fungicides that offer improved efficiency and lower environmental impact for controlling phytopathogenic fungi. In this study, a series of 20 novel thymol derivatives, incorporating a 1,2,3-triazole moiety, were synthesized via a three-step process, with the key step being the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The antifungal activity of these compounds was evaluated against , the etiological agent of papaya fruit and stem rot. Additionally, molecular docking was performed to assess the binding energy and interaction modes of these derivatives with the lanosterol 14α-demethylase (CYP51) enzyme. Docking results demonstrated that all derivatives bound to the catalytic pocket of CYP51 with lower binding energy (<-10 kcal/mol) compared to the azole fungicide tebuconazole (-8.2 kcal/mol) and the substrate lanosterol (-9.0 kcal/mol). The observed fungicidal activity is likely due to the occupancy of the entrance tunnel and active site of the CYP51 by these derivatives, thereby blocking lanosterol and its conversion into ergosterol.
基于唑类的杀菌剂是市场上使用最广泛且有效的药剂之一。然而，它们的滥用会导致药效降低和病原体抗性增加。这凸显了对新型杀菌剂的需求，这类杀菌剂在控制植物病原真菌方面应具有更高的效率和更低的环境影响。在本研究中，通过三步法合成了一系列包含1,2,3 - 三唑部分的20种新型百里酚衍生物，关键步骤是铜（I）催化的叠氮化物 - 炔烃环加成（CuAAC）反应。评估了这些化合物对番木瓜果实和茎腐病病原体的抗真菌活性。此外，进行了分子对接以评估这些衍生物与羊毛甾醇14α - 脱甲基酶（CYP51）的结合能和相互作用模式。对接结果表明，与唑类杀菌剂戊唑醇（-8.2 kcal/mol）和底物羊毛甾醇（-9.0 kcal/mol）相比，所有衍生物均以更低的结合能（<-10 kcal/mol）与CYP51的催化口袋结合。观察到的杀菌活性可能是由于这些衍生物占据了CYP51的入口通道和活性位点，从而阻止了羊毛甾醇及其向麦角甾醇的转化。
