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

  • J Agric Food Chem. 2025 Nov 12;73(45):28689-28699. doi: 10.1021/acs.jafc.5c07822.
Qing Han  1  2  3 ,  Yanqiu He  3 ,  Xiaomei Ma  4  5 ,  Yunjiang Zi  1  2 ,  Renxuan Zou  1  2 ,  Tianyu Feng  1  2 ,  Wei Zhao  3 ,  Yinliang Wang  4  5 ,  Hongxia Duan  1  2
Affiliations
  • 1. Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
  • 2. Key Laboratory of National Forestry and Grassland Administration on Pest Chemical Control, Beijing 100193, People's Republic of China.
  • 3. Institute of Plant Protection and Agro-Products Safety, Anhui Academy of Agricultural Sciences, Hefei 230000, People's Republic of China.
  • 4. Jilin Provincial Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun, Jilin 116000, People's Republic of China.
  • 5. Key Laboratory of Vegetation Ecology, MOE, Northeast Normal University, Changchun, Jilin 116000, People's Republic of China.
PMID: 41169121 DOI: 10.1021/acs.jafc.5c07822
Abstract

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.

Keywords
electrophysiology response; low bee-toxicity aphicidal sulfoximines; mode of action; nAChR subunit; rational design orientated by target.
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