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Pests represent an important impediment to efficient agricultural production and pose a threat to global food security. On the basis of our prior research focused on identifying insecticidal leads targeting insect ryanodine receptors (RyRs), we aimed to identify evodiamine scaffold-based novel insecticides. Thus, a variety of evodiamine-based derivatives were designed, synthesized, and assessed for their insecticidal activity against the larvae of Mythimna separata(M. separata) and Plutella xylostella(P. xylostella). The preliminary bioassay results revealed that more than half of the target compounds exhibited superior activity compared to evodiamine, matrine, and rotenone against M. separata. Among these, compound 21mdisplayed the most potent larvicidal efficiency, with a remarkable mortality rate of 93.3% at 2.5 mg/L, a substantial improvement over evodiamine (10.0% at 10 mg/L), matrine (10.0% at 200 mg/L), and rotenone (30.0% at 200 mg/L). In the case of P. xylostella, compounds 21mand 21odisplayed heightened larvicidal activity, boasting LC50values of 9.37 × 10–2and 0.13 mg/L, respectively, surpassing that of evodiamine (13.41 mg/L), matrine (291.78 mg/L), and rotenone (18.39 mg/L). A structure–activity relationship analysis unveiled that evodiamine-based derivatives featuring a cyclopropyl sulfonyl group at the nitrogen atom of the B ring and a fluorine atom in the E ring exhibited more potent larvicidal effects. This finding was substantiated by calcium imaging experiments and molecular docking, which suggested that 21mcould target insect RyRs, including resistant mutant RyRs of P. xylostella(G4946E and I4790M), with higher affinity than chlorantraniliprole (CHL). Additionally, cytotoxicity assays highlighted that the potent compounds 21i, 21m, and 21odisplayed favorable selectivity and low toxicity toward nontarget organisms. Consequently, compound 21memerges as a promising candidate for further development as an insecticide targeting insect RyRs.

Computer-aided molecular modeling was applied to design a series of Spodoptera frugiperdaRyR agonists. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. MD simulations in the complex with S. frugiperdanative, mutant RyR, and mammalian RyR1 under physiological conditions were used to validate the detailed binding mechanism. Binding free energy calculation by molecular mechanics generalized surface area (MM-GBSA) explained the role of key amino acid residues in ligand–receptor binding. Therefore, 14 new compounds were effectively designed and synthesized, and a bioassay indicated that compounds A-2and A-3showed comparable activity to that of chloranthraniliprole with LC50values of 0.27, 0.18, and 0.20 mg L–1, respectively, against S. frugiperda. Most target compounds also displayed good activity against Mythinma separataat 0.1 mg L–1. Molecular docking and MM-GBSA calculations demonstrated that A-3had a better binding capacity with native and mutant S. frugiperdaRyRs.

Three-dimensional quantitative structure–activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III band III yshowed similar activity against M. separataas chlorantraniliprole (LC50values: 0.21, 0.25, and 0.16 μg mL–1respectively). Compounds III bexhibited a 3-fold higher potency against P. xylostellathan chlorantraniliprole. For S. frugiperda, the potency of III aand III bwas 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III bcan dock well with mutated P. xylostellaRyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III bwas found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.

Pests are one of the major factors causing crop damage and food security problems worldwide. Based on our previous studies on the discovery of insecticidal leads targeting the ryanodine receptors (RyRs), a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was established to design and synthesize a series of anthranilic diamides containing a halogenated phenyl 3-trifluoroethoxypyrazole moiety. The preliminary bioassays disclosed that IIb, IIIb, and IIIfagainst Mythimna separatashowed comparable activity to chloranthraniliprole (LC50: 0.16, 0.16, 0.14, and 0.13 mg·L–1, respectively). More than half of the target compounds displayed good activity against Plutella xylostella,where IIIfwas the most active compound, 25 times more active than chloranthraniliprole (LC50: 6.0 × 10–6versus 1.5 × 10–4mg·L–1). For Spodoptera frugiperda, IIIfdisplayed slightly inferior potency to chlorantraniliprole (LC50: 0.47 versus 0.31 mg·L–1). For RyR mutants of S. frugiperda(G4891E, I4734M), compound IIIfcould show higher affinity than chlorantraniliprole according to the binding mode and energy in molecular docking experiments. Calcium imaging technique, molecular docking, density functional theory calculations, and electrostatic potential studies validated that the RyR was the target of the most active candidate IIIf, which deserves further development.

The diamide insecticides show exceptional activity against Lepidopterainsects via activation of ryanodine receptors (RyRs). In the present study, a series of anthranilic diamides containing a fluoroaniline moiety were designed, synthesized, and evaluated for insecticidal potency. Most titled compounds exerted moderate to remarkably high activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. The insecticidal activity of compound II land II acagainst M. separatawas 26.7 and 26.7% at 0.1 mg L–1, respectively, equivalent to that of chlorantraniliprole (0.1 mg L–1, 30.0%). Compounds II l, II y, and II zexhibited 8.0-, 1.8-, and 4.7-fold higher potency than chlorantraniliprole against P. xylostella, respectively, as compared with their LC50s. Compounds II kand II aashowed good insecticidal activity against S. frugiperdawith LC50of 0.56 and 0.46 mg L–1, respectively, comparable to that of the commercial insecticide chlorantraniliprole with LC50of 0.31 mg L–1. Calcium imaging experiments indicated RyRs as the action target. Molecular docking suggested a higher binding energy of 8.647 kcal/mol between II land the M. separataRyR than the 7.820 kcal/mol between chlorantraniliprole and the M. separataRyR. Meanwhile, the docking results of II lwith mutated P. xylostellaRyR at site G4946E showed that II lcould have a good inhibition effect on the resistant P. xylostella. The density functional theory calculations suggested the importance of the fluoroaniline moiety in potency. Those novel anthranilic diamides containing a fluorinated aniline moiety are good insecticidal candidates.

To discover novel target-based fungicidal candidates, a molecular design model was established with a three-dimensional (3D) structure of Rhizoctonia solanipyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22as a fungicidal lead. A series of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were rationally designed, synthesized, evaluated for their fungicidal performance, and validated for their mode of action. The in vitrobioassays with R. solaniindicated that compounds 5g, 5o, and 5zwith an EC50value ranging from 1.01 to 1.54 μg/mL displayed higher fungicidal activity than the positive control YZK-C22with its EC50of 3.14 μg/mL. Especially, 5oexhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorumwith its EC50value falling between 1.54 and 13.10 μg/mL. Like all positive controls, 5g, 5o, and 5zshowed excellent in vivogrowth inhibition against Pseudoperonospora cubensisat 200 μg/mL. Even though the PK enzymatic inhibition assay showed that 5owas approximately 2.6 times less active than YZK-C22(IC50: 29.14 vs11.15 μg/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5oand YZK-C22, and the docking results of interactions between RsPK and 5oor YZK-C22implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5ocould be used as a potent fungicidal lead for further optimization. The results of comparative molecular field analysis (CoMFA) provided a direction for further molecular design.

Insect ryanodine receptors (RyRs) are molecular targets of the anthranilic diamide insecticides. In the present study, a new series of anthranilic diamides containing a cyanophenyl pyrazole moiety were rationally designed by active-fragment assembly and computer-aided design using the 3D structure of Plutella xylostellaRyRs as a receptor and chlorantraniliprole as a ligand. Most of the titled compounds showed good toxicity against Mythimna separate, P. xylostella, and Spodoptera frugiperda. Compounds CN06, CN11, and CN16with corresponding LC50values of 0.15, 0.29, and 0.52 mg·L–1, respectively, against M. separateshowed comparable activity to that of chlorantraniliprole (0.13 mg·L–1). Surprisingly, CN06, CN11, and CN16with corresponding LC50values of 1.6 × 10–5, 3.0 × 10–5, and 2.8 × 10–5mg·L–1, respectively, against P. xylostellawere at least 5-fold more active than chlorantraniliprole (1.5 × 10–4mg·L–1). In the case of S. frugiperda, CN06, CN11, and CN16had good potency but lower than chlorantraniliprole in terms of LC50values (0.58, 0.54, and 0.56 mg·L–1versus 0.31 mg·L–1). Molecular docking of CN06and chlorantraniliprole to P. xylostellaRyRs validated the molecular design, and the calcium imaging technique further proved the potential target of CN06as RyRs. Compounds CN06, CN11, and CN16could be more effective than chlorantraniliprole in targeting the resistant RyR mutants of S. frugiperda(G4891E, I4734M) through the binding mode and energy obtained by molecular docking. Density functional theory calculations (DFT) and electrostatic potential (ESP) studies gave the structure–activity relationship. Compounds CN06, CN11, and CN16could be used as potent insecticide leads for further optimization.

To discover novel inhibitors of the complex I reduced nicotinamide adenine dinucleotide (NADH) oxidoreductase as fungicides, a series of 6-isothiazol-5-ylpyrimidin-4-amine-containing compounds were designed using a computer-aided pesticide design method and splicing of substructures from diflumetorim and isotianil. In vitro fungicidal bioassays indicated that compounds T17–T24showed high inhibitory activity against Rhizoctonia solaniwith an effective concentration (EC50) value falling between 2.20 and 23.85 μg/mL, which were more active than or equivalent to the lead diflumetorim with its EC50of 19.80 μg/mL. In vivo antifungal bioassays demonstrated that, at a concentration of 200 μg/mL, T7and T21showed higher inhibition against Pseudoperonospora cubensisthan all other compounds, while T23exhibited the highest inhibition against Sphaerotheca fuliginea. T23showed an approximately twofold lower inhibition potency against R. solanicomplex I NADH oxidoreductase than diflumetorim. Molecular docking and transcriptomic analyses indicated that T23and diflumetorim both might share the same mode of action, targeting NADH oxidoreductase. T23as a good fungicidal candidate against R. solaniis worthy of further investigation.

To increase the structural diversity of insecticides and meet the needs of effective integrated insect management, the structure of chlorantraniliprole was modified based on a previously established three-dimensional quantitative structure–activity relationship (3D-QSAR) model. The pyridinyl moiety in the structure of chlorantraniliprole was replaced with a 4-fluorophenyl group. Further modifications of this 4-fluorophenyl group by introducing a halogen atom at position 2 and an electron-withdrawing group (e.g., iodine, cyano, and trifluoromethyl) at position 5 led to 34 compounds with good insecticidal efficacy against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compound IV fagainst M. separatashowed potency comparable to that of chlorantraniliprole. IV pagainst P. xylostelladisplayed a 4.5 times higher potency than chlorantraniliprole. In addition, IV dand chlorantraniliprole exhibited comparable potencies against S. frugiperda. Transcriptome analysis showed that the molecular target of compound IV fis the ryanodine receptor. Molecular docking was further performed to verify the mode of action and insecticidal activity against resistant P. xylostella.

Succinate dehydrogenase inhibitors (SDHIs) are a class of fungicides targeting the pathogenic fungi mitochondrial SDH. Here, molecular docking, three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular dynamics (MD) simulations were used to guide SDHI innovation. Molecular docking was performed to explore the binding modes of SDH and its inhibitors. 3D-QSAR models were carried out on 33 compounds with activity against Rhizoctonia cerealis(R. cerealis); their structure–activity relationships were analyzed using comparative molecular field analysis and comparative molecular similarity indices analysis. MD simulations were used to assess the stability of the complexes under physiological conditions, and the results were consistent with molecular docking. Binding free energy was calculated through the molecular mechanics generalized born surface area method, and the binding free energy was decomposed. The results are consistent with the activity of bioassay and indicate that van der Waals and lipophilic interactions contribute the most in the molecular binding process. Afterward, we designed and synthesized 12 compounds under the guidance of the above-mentioned analyses, bioassay found that F9was active against R. cerealiswith the EC50value of 9.43 μg/mL, and F4, F5, and F9were active against Botrytis cinereawith an EC50values of 5.80, 3.17, and 1.63 μg/mL, respectively. They all showed good activity between positive controls of pydiflumetofen and thifluzamide. Our study provides new considerations for effective SDHIs discovery.