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Design, Synthesis, and Insecticidal Activity of 5,5-Disubstituted 4,5-Dihydropyrazolo[1,5‑a]quinazolines as Novel Antagonists of GABA Receptors

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journal contribution
posted on 03.12.2020, 17:07 by Xunyuan Jiang, Shuai Yang, Ying Yan, Fei Lin, Ling Zhang, Weijing Zhao, Chen Zhao, Hanhong Xu
To control the development of resistance to conventional insecticides acting as γ-aminobutyric acid (GABA) receptor antagonists (e.g., fipronil), new GABAergic 5,5-disubstituted 4,5-dihydropyrazolo­[1,5-a]­quinazolines were designed via a scaffold-hopping strategy and synthesized with a facile method. Among the 50 target compounds obtained, compounds 5a, 5b, 7a, and 7g showed excellent insecticidal activities against a susceptible strain of Plutella xylostella (LC50 values ranging from 1.03 to 1.44 μg/mL), which were superior to that of fipronil (LC50 = 3.02 μg/mL). Remarkably, the insecticidal activity of compound 5a was 64-fold better than that of fipronil against the field population of fipronil-resistant P. xylostella. Electrophysiological studies against the housefly GABA receptor heterologously expressed in Xenopus oocytes indicated that compound 5a could act as a potent GABA receptor antagonist, and IC50 was calculated to be 32.5 nM. Molecular docking showed that the binding poses of compound 5a with the housefly GABA receptor can be different compared to fipronil, which explains the effectiveness of compound 5a against fipronil-resistant insects. These findings have suggested compound 5a as a lead compound for a novel GABA receptor antagonist controlling field-resistant insects and provided a basis for further design, structural modification, and development of 4,5-dihydropyrazolo­[1,5-a]­quinazoline motifs as new insecticidal GABA receptor antagonists.