Novel 2-aminothiazole derivatives incorporating 9-alkyl purine moiety: design, synthesis, crystal structure, and bioactivity evaluation.

A series of 2-aminothiazole derivatives (3A1-3A30) containing 9-alkyl purine moiety were designed and synthesized to explore novel antibacterial agents with unique structures and potent antibacterial activity. The structures of target compounds were characterized using ¹H NMR, ¹³C NMR, and HRMS techniques. The structure of compound 3A12 was further elucidated through single crystal X-ray diffraction analysis. Results from antibacterial activity tests indicated that compound 3A7 exhibited a significant inhibitory effect on Xanthomonas oryzae pv. oryzicola (Xoc), with an EC₅₀ (half-maximal effective concentration) value of 25.5 μg/mL, which was more than three times higher than that of the control agent thiodiazole copper (EC₅₀ = 78.4 μg/mL). Compound 3A25 has a strong inhibitory effect on Xanthomonas axonopodis pv. citric (Xac), with significantly higher activity than thiodiazole copper in terms of EC₅₀ value (47.3 vs 92.1 µg/mL). Additionally, the EC₅₀ value of compound 3A7 against Pseudomonas syringae pv. actinidiae (Psa) was measured at 57.5 µg/mL, demonstrating superior efficacy relative to the control agents bismerthiazol (EC₅₀ = 92.9 µg/mL) and thiodiazole copper (EC₅₀ = 90.2 µg/mL). The antibacterial mechanism of compound 3A7 was examined through an investigation into the production of exopolysaccharides, alterations in membrane permeability, morphological changes in bacterial cells, and the development of a molecular docking model. Through a 100 ns molecular dynamics (MD) simulation, the stability of the binding between compound 3A7 and the AvrRxo1-ORF1 protein was confirmed. Furthermore, the chemical reactivity of potential bioactive compounds was evaluated using density functional theory (DFT).