Copper-Catalyzed Tunable Oxygenative Rearrangement of Tetrahydrocarbazoles.

Herein, we report a general copper-catalyzed method for the tunable oxygenative rearrangement of tetrahydrocarbazoles to cyclopentyl-bearing spiroindolin-2-ones and spiroindolin-3-ones. The method demonstrates excellent chemoselectivity, regioselectivity, and product control simply by using the H2O and O2 as oxygen source, respectively. This open-flask method is safe and simple to operate, and no other chemical oxidants are required. Besides, inspired from the unique pathway of 1, 2-migration rearrangement, a highly controllable hydroxylation of indoles for the construction of C3a-hydroxyl iminium indolines was also developed. Mechanistic experiments suggest that a single-electron transfer-induced oxidation process is responsible for the tunable selectivity control.

Discovery of a Novel Class of Acylthiourea-Containing Isoxazoline Insecticides against Plutella xylostella.

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.

A Potential Lead for Insect Growth Regulator: Design, Synthesis, and Biological Activity Evaluation of Novel Hexacyclic Pyrazolamide Derivatives.

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.

New lead discovery of insect growth regulators based on the scaffold hopping strategy.

Insect growth regulators (IGRs), which can interrupt or inhibit pest life cycles, are low-toxicity pesticides widely used in integrated pest management (IPM). Ecdysone analogues and chitinase inhibitors are familiar IGRs that have attracted considerable attention because of their unique modes of action and low toxicity to non-target organisms. To find new and highly effective candidate IGRs with novel mechanisms, D-08 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) was chosen as a lead compound, and a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized using the scaffold hopping strategy. The bioassay showed that III-27 (N-(2-methylphenethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) had excellent activity against Plutella xylostella. Protein verification and molecular docking indicated that III-27 could act on both the ecdysone receptor (EcR) and Ostrinia furnacalis chitinase (Of ChtI) and is a promising new lead IGRs. The interaction mechanism of III-27 with EcR and Of ChtI was then studied by molecular docking. These results provide important guidance for the study of new dual-target IGRs.

Synthesis and bioactivities of novel piperazine-containing 1,5-Diphenyl-2-penten-1-one analogues from natural product lead.

A series of novel 1,5-Diphenyl-2-penten-1-one analogues (7a-h, 8a-h) with piperazine moiety have been designed and synthesized on the basis of natural product 1,5-Diphenyl-2-penten-1-one (I). All the synthesized compounds were evaluated in vitro for anti-plant pathogenic fungi activities and insecticidal activities. The results indicated that most of these analogues exhibited moderate antifungal activities and moderate to good insecticidal activities. Amongst them, the most potent 7c, 7e and 7h keep a mortality of 100% against larva of mosquito at the concentration of 1mg/L. Initial structure-activity relationship (SAR) analysis showed that, a methyl group can influence the biological activities of these compounds significantly, the compounds with N'-unsubstituted piperazine showed much better antifungal activities and larvicidal activity against mosquito than the compounds with N'-methylated piperazine. In addition, the larvicidal activity against mosquito had sharply decline when the substituent on benzene ring was changed from 4-position to 2 or 3-position.

Design, Synthesis, and Insecticidal Activity of Isoxazoline Derivatives Incorporating an Acylhydrazine Moiety.

The long-term use of agricultural insecticides has led to the development of resistant strains. In this context, the isoxazoline structure has become an active area of pesticide research owing to its wide insecticidal spectrum, nontoxicity to mammals, and lack of cross-resistance with known insecticides. In the present study, based on the discovery of compound G22 in our previous work, a series of novel isoxazoline compounds containing acylhydrazine were designed and synthesized using a scaffold hopping strategy. The insecticidal activities of the target compounds were assessed, and compound L17 (LC50 = 0.489 mg/L) showed insecticidal activity against Spodoptera frugiperda superior to those of the commercial insecticides indoxacarb (LC50 = 3.14 mg/L) and fluralaner (LC50 = 0.659 mg/L). Theoretical calculations indicated that the introduction of acylhydrazine plays an important role in the biological activity of the target compounds. Furthermore, the enzyme-linked immunosorbent assay and molecular docking results indicated that L17 may act on the GABA receptor of the target insect. These results indicated that L17 is a potential candidate compound for controlling S. frugiperda populations in agriculture.

Discovery of Novel Isoxazoline Derivatives Containing Diaryl Ether against Fall Armyworms.

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 (LC50 = 1.69 mg/L) exhibited excellent insecticidal activity against S. frugiperda, which was better than those of commercial fipronil (LC50 = 70.78 mg/L) and indoxacarb (LC50 = 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.

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Compounds That Contain Meta-diamides against Fall Armyworm (Spodoptera frugiperda).

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.

Discovery of Novel Isoxazoline Compounds that Incorporate a para-Diamide Moiety as Potential Insecticidal Agents against Fall Armyworm (Spodoptera frugiperda).

Spodoptera frugiperda is a major migratory agricultural pest, which seriously impedes agricultural production around the world. To discover potent compounds against S. frugiperda, a number of novel isoxazoline derivatives were designed and synthesized and created on account of the identified lead compound F32 (4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(3-propionamidophenyl)benzamide). Based on the three-dimensional quantitative structure-activity relationship of those compounds, the compound G22 (N-(4-acetamidophenyl)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide) was developed. A bioassay showed that G22 is highly lethal to S. frugiperda (LC50 = 1.57 mg/L), a more effective control than insecticides fipronil (LC50 = 78.8 mg/L) and chlorantraniliprole (LC50 = 1.60 mg/L). Field trials were also implemented to identify candidate agents. Furthermore, from the insect γ-aminobutyric acid (GABA) enzyme-linked immunosorbent assay, it is obvious that G22 could up-regulate the expression of GABA of insects, which showed a similar result to fipronil. The analysis of molecular docking exhibited that the hydrophobic effect and hydrogen bonds play key roles in the combination between G22 with GABA receptors. This study provides a potent isoxazoline candidate compound for the S. frugiperda control.

Design, synthesis and antifungal/anti-oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors.

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.

Design, Synthesis, and Biological Activity of Novel Heptacyclic Pyrazolamide Derivatives: A New Candidate of Dual-Target Insect Growth Regulators.

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.