Structural optimization based on 4,5-dihydropyrazolo[1,5-a]quinazoline scaffold for improved insecticidal activities

Abstract

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.