Design,Synthesis,and Insecticidal Activity Of 4,5-dihydropyrazolo[1,5-a]quinazolines As Novel Insecticides

The insect GABA receptors(GABARs)are proven to be safe and important targets for insecticides.Several representative insecticides targeting GABARs,have been banned or suffering regulatory issues because of their potential toxicity and increased resistance.Recently,4,5-dihydropyrazolo[1,5-a]quinazolines were identified as novel high-affinity ligands for GABA_Areceptors in human.Owing to the high homology of GABA receptors between human and insects,it is possible that4,5-dihydropyrazolo[1,5-a]quinazolines can also act as novel chemotype insecticides targeting insect GABA receptors.In order to control the development of resistance to conventional GABAR antagonist insecticides(e.g.,fipronil),new 5,5-disubstituted4,5-dihydropyrazolo[1,5-a]quinazolines were designed via scaffold hopping strategy to generate analogs of fiprole insecticide.The novel 5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazolines were efficiently constructed,for the first time,via cascade aza-Michael addition/Truce-Smiles rearrangement/intramolecular S_NAr cyclization of 5-amine-1H-phenylpyrazoles with olefins in good yields even on gram scale.In this divergent reaction route,an unexpected Truce-Smiles rearrangement was controllably involved depending on the substrate and prompted the process of cascade reaction which was verified by DFT calculations.This practical and one-pot approach not only utilizes common versatile starting materials,but also proceeds under mild conditions without the usage of any catalysts.In addition,more5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazoline derivatives were designed on the basis of bioassays and synthesized with site-selective transformations of the distalis methyl esters on compounds 5aa and 5ac.Insecticidal activities of the synthesized 5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazoline derivatives were systematically examined using susceptible strain and field-resistant population of Plutella xylostella.Among all the target compounds,especially compounds 5aa,5ac,7a and 7g showed excellent insecticidal activities against the susceptible strain of P.xylostella(LC₅₀values ranging from 1.03 to 1.44?g/m L),which were superior to that of fipronil(LC₅₀=3.02?g/m L).Remarkably,insecticidal activity of compound 5aa was 64-fold better than fipronil against field population of P.xylostella,which has 68.9-fold resistance to fipronil.Bioassay results showed that compound 5aa exhibits no cross-resistance with fipronil and thus emerges as new lead molecule for novel insecticides.The electrophysiological experiments against housefly GABARs expressed in Xenopus oocytes indicated that compound 5aa could act as a potent GABA antagonist,with IC₅₀value of 32.5 n M.Molecular docking showed that the binding pose of compound 5aa with GABARs can be different compared to fipronil,which explains the effectiveness of compound 5aa against fipronil-resistant insects.In conclusion,we have disclosed here the first synthesis of 5,5-disubstituted4,5-dihydropyrazolo[1,5-a]quinazolinesviacascadereactionof5-amine-1H-phenylpyrazoles with olefins under mild conditions without the usage of any catalysts.Furthermore,this work have identified compound 5aa to be a novel and potent insect GABARs antagonist,highlighting the considerable potential for a new class of insecticide being effective managing insect resistance caused by indiscriminate usage of fipronil and provided a basis for further design,structural modification,and development of4,5-dihydropyrazolo[1,5-a]quinazoline motif as new insecticidal GABARs antagonist.