BACKGROUND: The aphid alarm pheromone, (E)-⊎-farnesene (E⊎F), is a natural product secreted from the aphid cornicle as a signal to warn companions of danger. Odorant binding proteins (OBPs) are the vital targets in insect signal transduction pathways. To improve bioactivity of E⊎F as more economic and stable aphid control agents, E⊎F derivatives containing an active substructure, salicylic acid moiety, were designed, synthesized, and evaluated for their bioactivities in a structure-function study under laboratory conditions. RESULTS: E⊎F derivatives, (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methylbenzoate and (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methoxybenzoate showed outstanding aphid-repellent activity at a dose of 5 ∼g against Acyrthosiphon pisum (repellency proportions of 67.3% and 71.2%, respectively) and Myzus persicae (repellency proportions of 80.0% and 74.4%, respectively) in laboratory. E⊎F and most of its derivatives bound strongly to ApisOBP9 with a higher affinity than those of the reported potential targets AphisOBP3 and ApisOBP7. The binding affinities to these three ApisOBPs were generally consistent with the in vivo aphid-repellent activity. A molecular docking study suggested that the hydrophobic effect was crucial for the interactions between the derivatives and the OBPs. CONCLUSION: New E⊎F derivatives containing salicylic acid moiety and their repellent activity, binding mechanism with three potential OBPs are presented. A new OBP, ApisOBP9, was characterized as a potential E⊎F and E⊎F derivatives binding protein for the first time. The hydrophobic nature of these analogues is responsible for their activity. Two analogues 3b and 3e with outstanding aphid-repellent activity could be new leads for aphid control agents.

The insect chitinase Of ChtI from the agricultural pest Ostrinia furnacalis (Asian corn borer) is a promising target for green insecticide design. Of ChtI is a critical chitinolytic enzyme for the cuticular chitin degradation at the stage of molting. In this study, piperine, a natural amide compound isolated from black pepper, Piper nigrum L., was discovered for the first time to have inhibitory activity toward Of ChtI. The compound−enzyme interaction was presumed to take place between the piperine benzo [d][1,3] dioxole skeleton and subsite −1 of the substrate-binding pocket of Of ChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of Of ChtI, compounds 5a−f were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds 5a−f (K i = 1.03−2.04 μM) exhibited approximately 40−80-fold higher inhibitory activity than the lead compound piperine (I) (K i = 81.45 μM) toward Of ChtI. The inhibitory mechanism of the piperonyl butenolide compounds was elucidated by molecular dynamics, which demonstrated that the introduced butenolide skeleton improved the binding affinity to Of ChtI. Moreover, the in vivo activity assay indicated that these compounds also displayed moderate insecticidal activity toward O. furnacalis. This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting Of ChtI.

Laccase is a novel target for fungicides. We previously developed a new fungicide, 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y), as a laccase inhibitor. The introduction of active groups of natural products into the framework of a pesticide molecular structure is an effective method for discovering active lead compounds, and it has applications in the discovery of new pesticides. In this work, PMDD-5Y was selected as a lead compound, and we designed and synthesized a series of novel sulfonyl hydrazide derivatives containing the natural product scaffold 1,2,3,4-tetrahydroquinoline. The new compounds had antifungal activities against several fungi, especially Valsa mali and Sclerotinia sclerotiorum. One compound (4bl) displayed very good in vitro activity against S. sclerotiorum and V. mali, with EC 50 values of 3.32 and 2.78 μg/mL, respectively. The results of an enzyme activity assay showed that 4bh had the best inhibitory activity against laccase, with an EC 50 value of 14.85 μg/mL. This was more active than the lead compound PMDD-5Y and the positive control cysteine. Using a molecular docking method, we studied the binding mode of the title compounds with laccase. The structural features of these new laccase inhibitors as fungicides will advance research and impact the field of discovering more potent fungicides to control diseases in agriculture.

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