Target-based design, synthesis and biological activity of new pyrazole amide derivatives

Based on the similarities in the conformation of VS008 (N-(4-methylphenyl)-3-(tert-butyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide) and BYIO6830 (N′-(3,5-dimethylbenzoyl)-N′-tert-butyl-5-methyl-2,3-dihydro-1,4-benzodioxine-6-carbohydrazide) bound to the active site of the EcR subunit of the ecdysone receptor (EcR)-ultraspiracle protein (USP) heterodimeric receptor, a series of new pyrazole amide derivatives were designed and synthesized. Their structures were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. Results from a preliminary bioassay revealed that two of the pyrazole derivatives exhibited promising insecticidal activity. Specifically, compounds 6e and 6i exhibited good activity against Helicoverpa armigera (cotton bollworm) at low concentration. Symptoms displayed by tebufenozide-treated H. armigera were identical with those displayed by its treated counterpart. 6i showed the same poisoning symptoms as those of tebufenozide. In addition, results from molecular docking result indicated that the binding modes of 6e and 6i at the active site of the EcR subunit of the heterodimeric receptor were similar to that of the bound tebufenozide.

Graphical abstractBased on the binding conformation of ligands with the ecdysone receptors (EcRs), a series of new pyrazole amide derivatives were designed and prepared. Several compounds, for example 6e and 6i, had good insecticidal activity. Helicoverpa armigera treated with 6i showed the same poisoning symptoms as those of tebufenozide. Furthermore, molecular docking and molecular dynamics studies revealed that the binding modes of 6e or 6i with the EcR subunit were similar to that of tebufenozide. These results gave the useful guide to discover new IGRs.Figure optionsDownload full-size imageDownload as PowerPoint slide