Design and synthesis of mesoionic compounds containing benzoxacycle for the control of piercing-sucking pests

Piercing-sucking pests cause significant agricultural losses, and widespread neonicotinoid use has led to resistance and ecological concerns. Mesoionic compounds show broad-spectrum insecticidal activity with low cross-resistance, yet the mechanism and potential of tetrahydrothiazolo[3,2-a]pyrimidine mesoionic scaffolds against these pests remain largely unexplored. Here, a series of novel tetrahydrothiazolo[3,2-a]pyrimidine mesoionics containing a benzoxacycle moiety were designed, synthesized, and evaluated for insecticidal activity against Megoura crassicauda (M. crassicauda) and Sogatella furcifera (S. furcifera). All compounds showed notable bioactivity, with H₁ displaying the highest aphicidal potency (LC₅₀ = 1.08 mg/L) and its enantiomer (R)-H₁ exhibiting markedly enhanced activity (LC₅₀ = 0.31 mg/L), superior to triflumezopyrim (TFM, LC₅₀ = 2.13 mg/L) and comparable to fenmezoditiaz (LC₅₀ = 0.16 mg/L). Acute contact toxicity assays demonstrated that (R)-H₁ was substantially less toxic to honeybees (LD₅₀ = 4.58 μg/bee) than TFM (LD₅₀ = 0.55 μg/bee) and fenmezoditiaz (LD₅₀ = 1.28 μg/bee). Mode of action studies, including enzyme activity assays and ELISA, suggest that (R)-H₁ interferes with the neural function of aphids. DFT calculations and molecular docking further support the stable, stereoselective binding of (R)-H₁ to AChBP, providing a molecular basis for the observed enantioselective activity. Collectively, these findings highlight (R)-H₁ as a promising lead for developing environmentally benign insecticides targeting piercing-sucking pests.