Design and Optimization of Novel Sulfoximines as Low Bee-Toxicity Aphicides Targeting the Mpα1/ratβ2 Complex.

Targeting the insect nicotinic acetylcholine receptor (nAChR) is recognized as a validated strategy for developing novel insecticides. This study employed the Mpα1/ratβ2 complex to rationally design sulfoximine derivatives with enhanced efficacy against Myzus persicae. Based on the binding cavity and the interaction of the low bee-toxicity insecticide flupyradifurone with Amelα1/ratβ2, lead compound 7g was optimized. Two novel series (I-01∼30 and II-01∼16) were synthesized via bridge-chain shortening or fluorine atom introduction. Thereinto, compound II-08 exhibited better aphicidal activity (LC50 = 53.4 mg/L) and Mpα1/ratβ2 sensibility (EC50 = 0.111 μM) versus I-14 (LC50 = 77.6 mg/L, EC50 = 0.220 μM), which indicated that aphicidal efficiency could be related to the two-electrode voltage clamp responses on Mpα1/ratβ2. Moreover, representative sulfoximines I-09, I-14, 1-15, I-23, and II-08 showed essential nontoxicity (IV, LD50 > 100 μg/bee at 48 h) toward Apis mellifera and lower agonist responses on Amelα1/ratβ2 than sulfoxaflor. Critical hydrogen-bond donors (Lys144 and Ile134) in Mpα1 were identified for structural optimization to improve aphicidal potency. This work provides a solid rational design strategy for developing novel insecticides targeting the Mpα1/ratβ2 complex.