Design, synthesis, and antimicrobial evaluation of novel 1,2,4-trizaole thioether derivatives with a 1,3,4-thiadiazole skeleton

The aim of this study was to design and synthesize 17 novel 1,2,4-triazole thioether derivatives containing 1,3,4-thiadiazole thioether. Bioactivity assays indicated that several target compounds exhibited moderate to good antifungal and antibacterial activities. Notably, compound 9d demonstrated significantly stronger antifungal activity against <i>Trichoderma</i> sp. in <i>Morchella esculenta</i> (TSM) and <i>Mucor</i> sp. in <i>Dictyophora rubrovalvata</i> (MSD), with EC₅₀ values of 9.25 and 12.95 μg mL^-1, respectively, compared to the commercial fungicide pyrimethanil, which had EC₅₀ values of 35.29 and 15.51 μg mL^-1. Furthermore, compound 9d found to have strong antibacterial activity against <i>Pseudomonas syringae</i> pv. <i>actinidiae</i> (PSA) <i>in vitro</i>, with an EC₅₀ of 9.34 μg mL^-1, markedly superior to that of thiodiazole copper (81.74 μg mL^-1). Additionally, the <i>in vivo</i> anti-PSA assessment revealed therapeutic and protective activities at 200 μg mL^-1 of 59.39% and 79.33%, respectively, outperforming thiodiazole copper (38.91% and 67.64%, respectively). According to molecular docking simulations the interaction between compound 9d and FtsZ was mainly due to hydrogen bond formations with GLU-296, ARG-301, LYS-188, ASP-29 and GLY-30. This report suggests that these novel 1,2,4-triazole thioether derivatives featuring a 1,3,4-thiadiazole skeleton may effectively mitigate fungal and bacterial threats to plants.