The long-term and irrational application of insecticides has increased the rate of development of pest resistance and caused numerous environmental issues. To address these problems, our previous work reported that 4,5-dihydropyrazolo[1,5-a]quinazoline (DPQ) is a class of gelled heterocyclic compounds that act on insect γ-aminobutyric acid receptors (GABAR). DPQ scaffold has no cross-resistance to existing insecticides, so the development of this scaffold is an interesting task for integrated pest management. In the present study, a novel series of 4,5-dihydropyrazolo[1,5-a]quinazolines (DPQs) were designed and synthesized based on pyraquinil, a highly insecticidal compound discovered in our previous work. Insecticidal activities of the target compounds against diamondback moth (Plutella xylostella), beet armyworm (Spodoptera exigua), fall armyworm (Spodoptera frugiperda), and red imported fire ant (Solenopsis invicta Buren) were evaluated. Compounds 6 and 12 showed the best insecticidal activity against Plutella xylostella (P. xylostella) (LC₅₀ = 1.49 and 0.97 mg/L), better than pyraquinil (LC₅₀ = 1.76 mg/L), indoxacarb and fipronil (LC₅₀ = 1.80 mg/L). Meanwhile, compound 12 showed slow toxicity to Solenopsis invicta Buren (S. invicta), with a 5 d mortality rate of 98.89% at 0.5 mg/L that is similar to fipronil. Moreover, Electrophysiological studies against the PxRDL1 GABAR heterologously expressed in Xenopus oocytes indicated that compound 12 could act as a potent GABA receptor antagonist (2 μΜ, inhibition rate, 68.25%). Molecular docking results showed that Ser285 (chain A) and Thr289 (chain D) of P. xylostella GABAR participated in hydrogen bonding interactions with compound 12, and density functional theory (DFT) calculations suggested the importance of pyrazolo[1,5-a]quinazoline core in potency. This systematic study provides valuable clues for the development of DPQ scaffold in the field of agrochemicals, and compound 12 can be further developed as an insecticide and bait candidate.

长期不合理的杀虫剂使用，增加了害虫抗药性的发展速度，引发了众多的环境问题。为了解决这些问题，我们前期的工作报道了4,5-二氢吡唑并[1,5- a ]喹唑啉（DPQ）是一类作用于昆虫γ-氨基丁酸受体（GABAR）的凝胶杂环化合物。DPQ支架与现有杀虫剂没有交叉抗性，因此该支架的开发是害虫综合防治的一项有趣的任务。在本研究中，基于吡喹啉（我们之前的工作中发现的一种高杀虫化合物），设计并合成了一系列新型4,5-二氢吡唑并[1,5- a ]喹唑啉（DPQ）。评估了目标化合物对小菜蛾（Plutella xylostella ）、甜菜夜蛾（Spodoptera exigua ）、草地贪夜蛾（Spodoptera frugiperda ）和红火蚁（Solenopsis invicta Buren）的杀虫活性。化合物6和12对小菜蛾（ P. xylostella ）的杀虫活性最好（LC ₅₀  = 1.49和0.97 mg/L），优于吡喹啉（LC ₅₀  = 1.76 mg/L）、茚虫威和氟虫腈（LC ₅₀  = 1.80）毫克/升）。同时，化合物12对红火蚁( S. invicta )表现出缓慢的毒性，在0.5 mg/L浓度下5 d死亡率为98.89%，与氟虫腈相似。此外，针对非洲爪蟾卵母细胞中异源表达的Px RDL1 GABAR的表明，化合物12可以充当有效的GABA受体拮抗剂（2μM，抑制率，68.25%）。分子对接结果表明，小菜蛾GABAR的Ser285（A链）和Thr289（D链）参与了与化合物12的氢键相互作用，密度泛函理论（DFT）计算提示了吡唑并的重要性[1,5- a ]喹唑啉核心的效力。该系统研究为DPQ支架在农用化学品领域的开发提供了有价值的线索，化合物12可进一步开发为杀虫剂和诱饵候选药物。