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

Abstract

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 Trichoderma sp. in Morchella esculenta (TSM) and Mucor sp. in Dictyophora rubrovalvata (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 Pseudomonas syringae pv. actinidiae (PSA) in vitro, with an EC₅₀ of 9.34 μg mL^-1, markedly superior to that of thiodiazole copper (81.74 μg mL^-1). Additionally, the in vivo 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.

Fig. 1. Structures of some commercialized agricultural agents containing triazole moieties.

Fig. 2. Our team synthesized derivatives featuring 1,2,4-triazole thioether and 1,3,4-thiadiazole thioether during the initial phase.

Fig. 3. The molecular design involves 1,2,4-triazole thioether derivatives that incorporate a 1,3,4-thiadiazole backbone.

Scheme 1. Preparation method of target compounds 9a–9q.

Fig. 4. In vivo curative and protection efficacy of compound 9d (200 mg l⁻¹) against PSA infection.

Fig. 5. Scanning electron microscopy (SEM) morphology of PSA treated with compound 8d ((A) 8d, 10 μm; (B) 8d, 5 μm; (C) 8d, 3 μm; (D) CK, 10 μm; (E) CK, 5 μm; (F) CK, 3 μm).

Fig. 6. The stimulated molecular docking of 9d towards FtsZ. ((A) Three-dimensional model of FtsZ. (B and C) The optimal conformation of compound 9d docks with the binding pocket of FtsZ. (D) The binding mode and intermolecular interaction of compound 9d and FtsZ).