Discovery of Novel 2,4,5-Trisubstituted Oxazoline Derivatives as Potent Acaricidal Agents.

To overcome the high toxicity of etoxazole to aquatic invertebrates and its limited structural diversity while preserving its potent acaricidal activity, we successfully designed and synthesized 27 novel 2,4,5-trisubstituted oxazoline derivatives and systematically assessed their acaricidal activity. Among these, compounds 12q (LC50 = 0.84 mg/L) and 12u (LC50 = 0.74 mg/L) exhibited moderate ovicidal activity. Notably, compound 12aa exhibited good ovicidal (LC50 = 0.14 mg/L) and larvicidal activities (LC50 = 0.09 mg/L), highlighting its potential as a lead compound. Potential surface calculations and molecular docking studies indicated that differences in the lipophilicity of oxazoline derivatives as well as variations in their binding conformations within chitin synthase 1 of Tetranychus cinnabarinus (TcCHS1), might account for the observed differences in biological activity. Additionally, density functional theory (DFT) calculations further supported the design rationale. Zebrafish toxicity assays revealed that compounds 12q, 12u, and 12aa exhibited significantly lower acute toxicity, underscoring their potential as a safer alternative for pest management. Our current study has identified a novel 2,4,5-trisubstituted oxazoline scaffold with moderate acaricidal activity and reduced toxicity to zebrafish.