Design and Synthesis of Indole-Containing Tetrahydrothiazolo[3,2-a]pyrimidine Mesoionics against Hemipteran Pests

Mesoionic insecticides have emerged as promising pest nAChR modulators devoid of cross-resistance with neonicotinoids, demonstrating exceptional efficacy against sap-feeding insects. Nevertheless, the tetrahydrothiazolo[3,2-a]pyrimidine structure remains underexplored within this chemotype. Here, we report an indole-based scaffold hopping of tetrahydrothiazolo[3,2-a]pyrimidine, which leads to the development of a series of novel mesoionics. Their insecticidal potency is evaluated against the hemipteran pest Acyrthosiphon pisum (A. pisum) and Sogatella furcifera (S. furcifera). Derivative G1 exhibits excellent aphicidal activity (LC50 = 5.11 mg/L), comparable to triflumezopyrim (TFM) (3.71 mg/L) though less than fenmezoditiaz (1.03 mg/L). Chirally resolved (R)-G1 displays enhanced efficacy against A. pisum (LC50 = 2.12 mg/L). Notably, G1 demonstrates significantly lower acute contact toxicity to honeybees (LD50 = 27.66 μg/bee) versus TFM (highly toxic, 0.66 μg/bee) and fenmezoditiaz (moderately toxic, 5.12 μg/bee). Enzymatic assays, ELISA, and proteomics suggest G1’s disruptive impacts on neuronal pathways. Molecular docking shows strong binding of (R)-G1 to Aplysia californica AChBP via hydrogen bonds with residues IleC106, TrpD147, and TyrD195. This study identifies G1 as a potent insecticide lead with favorable pollinator safety.