Insect growth regulators (IGRs) can cause abnormal growth and development in insects, resulting in incomplete metamorphosis or even death of the larvae. Ecdysone receptor (EcR) and chitinase in insects play indispensable roles in the molting process. Ecdysone analogues and chitinase inhibitors are considered as potential IGRs. In order to find new and highly effective IGR candidates, based on the structure–activity relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)­phenyl)-1-phenyl-1H-pyrazole-5-carboxamide) discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized. The bioassay results demonstrated that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)­phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta­[c]­pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg·L–1) and Mythimna separata (100% mortality at 2.5 mg·L–1). Furthermore, protein validation indicated that D-27 acts not only on the EcR but also on chitinase Of ChtI. Molecular docking and molecular dynamics simulation explained the vital factors in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting point for discovering a novel type of IGRs.

BACKGROUND Succinate dehydrogenase inhibitors (SDHIs) play an increasingly important role in controlling plant diseases. However, the similar structures of SDHIs result in rapid development of cross‐resistance development and a clear bottleneck of poor activity against oomycetes, therefore the need to seek new SDHI fungicides with novel structures is urgent. RESULTS Innovative pyrazolyl oxime ethers were designed by replacing amide with oxime ether based on the succinate dehydrogenase (SDH) structure, and 19 pairs of Z‐ and E‐isomers were efficiently prepared for the discovery of SDHI compounds with a novel bridge. Their biological activities against four fungi and two oomycetes were evaluated, and substantial differences were observed between the Z‐ and E‐ isomers of the title compounds. Furthermore, most of these compounds exhibited remarkable activities against Rhizoctonia solani with EC50 values of less than 10 mg L−1 in vitro, and bioassay in vivo further confirmed that E‐I‐6 exhibited good protective efficacy (76.12%) at 200 mg L−1. In addition, Z‐I‐12 provided better activity against the oomycetes Pythium aphanidermatum and Phytophthora capsici (EC50 = 1.56 and 0.93 mg L−1) than those of boscalid. Moreover, E‐I‐12 exhibited excellent SDH inhibition (IC50 = 0.21 mg L−1) thanks to its good binding ability to the SDH by hydrogen‐bonding interactions, π‐cation interaction and hydrophobic interactions. CONCLUSION Novel pyrazolyl oxime ethers have the potential as SDHI compounds for future development, and the strategy of replacing an amide bond with oxime ether may offer an alternative option in SDHI fungicide discovery.

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Fall armyworm (Spodoptera frugiperda) is a major migratory pest around the entire world that causes severe damage to agriculture. We designed and synthesized a series of novel isoxazoline derivatives based on the previously discovered active compound H13 to find new and effective candidates against S. frugiperda. Most of them showed excellent insecticidal activity. In addition, a three-dimensional quantitative structure–activity relationship model was established, and compound F32 was designed and synthesized based on the results. The bioassay result showed that compound F32 exhibited excellent activity against S. frugiperda (LC50 = 3.46 mg/L), which was substantially better than that of the positive control fipronil (LC50 = 78.8 mg/L). Furthermore, an insect γ-aminobutyric acid (GABA) enzyme-linked immunosorbent assay indicated that F32 can upregulate the content of GABA in insects in a manner similar to that of fipronil. Molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are vital factors between the binding of F32 and receptors. All of these results suggest that compound F32 could be employed as a novel isoxazoline lead compound to control S. frugiperda.

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