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.
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.
Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) hexacyclic pyrazolamide derivatives were designed and synthesized by reducing the heptacycle and inserting small flexible linkers on the basis of the previously discovered dual-target compound D-27 acting simultaneously on EcR and Ostrinia furnacalis chitinase (OfChtI). Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda, and Ostrinia furnacalis larvae were evaluated. The results revealed that the insecticidal activity was not significantly enhanced when the heptacycle on the pyrazole ring was reduced to a hexacycle. However, the insertion of an additional methylene spacer between the substituted phenyl ring and the amide bond can improve the insecticidal activity. Among the derivatives, the most potent compound, 6j, exhibited promising insecticidal activities against P. xylostella and S. frugiperda. Further protein binding assays and molecular docking indicated that 6j could target both EcR and OfChtI, and is a potential lead compound for IGRs. The present work provides valuable clues for the development of new dual-target IGRs.
With the continuous evolution of insect resistance, it is a tremendous challenge to control the fall armyworm (Spodoptera frugiperda) with traditional insecticides. To solve this pending issue, a series of novel isoxazoline derivatives containing diaryl ether structures were designed and synthesized, and most of the target compounds exhibited excellent insecticidal activity. Based on the three-dimensional quantitative structure−activity relationship (3D-QSAR) model analysis, we further optimized the molecular structure with compound L35 obtained and tested for its activity. Compound L35 (LC 50 = 1.69 mg/L) exhibited excellent insecticidal activity against S. frugiperda, which was better than those of commercial fipronil (LC 50 = 70.78 mg/L) and indoxacarb (LC 50 = 5.37 mg/L). The enzyme-linked immunosorbent assay showed that L35 could upregulate the levels of GABA in insects. In addition, molecular docking and transcriptomic results also indicated that compound L35 may affect the nervous system of S. frugiperda by acting on GABA receptors. Notably, through high-performance liquid chromatography (HPLC), we were able to obtain the two enantiomers of compound L35, and the insecticidal activity test revealed that S-(+)-L35 was 44 times more active than R-(−)-L35 against S. frugiperda. This study established the chemistry basis and mechanistic foundations for the future development of pesticide candidates against fall armyworms.
Isoxazoline structures are widely found in natural products and are rich in biological activities. This study discloses the development of a series of novel isoxazoline derivatives by introducing acylthiourea fragments to access insecticidal activity. All synthetic compounds were examined for their insecticidal activity against Plutella xylostella, with results showing moderate to strong activity. Based on this, the structure–activity relationship analysis was carried out via the constructed three-dimensional quantitative structure–activity relationship model to further guide the structure optimization, resulting in the optimal compound 32. The LC50 of compound 32 against Plutella xylostella was 0.26 mg/L, demonstrating better activity than the positive control, ethiprole (LC50 = 3.81 mg/L), avermectin (LC50 = 12.32 mg/L), and compounds 1–31. The insect GABA enzyme-linked immunosorbent assay demonstrated that compound 32 might act on the insect GABA receptor, and the molecular docking assay further illustrated the mode of action of compound 32 with the GABA receptor. In addition, the proteomics analysis indicated that the action of compound 32 on Plutella xylostella was multi-pathway.
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