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 xylostella RyRs 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 CN16 with corresponding LC50 values of 0.15, 0.29, and 0.52 mg·L–1, respectively, against M. separate showed comparable activity to that of chlorantraniliprole (0.13 mg·L–1). Surprisingly, CN06, CN11, and CN16 with corresponding LC50 values of 1.6 × 10–5, 3.0 × 10–5, and 2.8 × 10–5 mg·L–1, respectively, against P. xylostella were at least 5-fold more active than chlorantraniliprole (1.5 × 10–4 mg·L–1). In the case of S. frugiperda, CN06, CN11, and CN16 had good potency but lower than chlorantraniliprole in terms of LC50 values (0.58, 0.54, and 0.56 mg·L–1 versus 0.31 mg·L–1). Molecular docking of CN06 and chlorantraniliprole to P. xylostella RyRs validated the molecular design, and the calcium imaging technique further proved the potential target of CN06 as RyRs. Compounds CN06, CN11, and CN16 could 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 CN16 could be used as potent insecticide leads for further optimization.
Natural products are one of the resources for discovering novel fungicidal leads. As a natural fungicide, osthole was used as a coumarin-based lead compound for the development of novel fungicides. Here, a series of 3,4-dichloroisothiazolecontaining 7-hydroxycoumarins were rationally designed, synthesized, and characterized by introducing a bioactive substructure, 3,4-dichloroisothiazole, into the coumarin skeleton. In vitro bioassay indicated that compound 7g displayed good activity against Rhizoctonia solani, Physalospora piricola, Sclerotinia sclerotiorum, and Botrytis cinerea. Its median effective concentration (EC 50 ) value against each of these fungi fell between 0.88 and 2.50 μg/mL, which was much lower than that of osthole against the corresponding pathogen (between 7.38 and 74.59 μg/mL). In vivo screening validated that 7k exhibited 100%, 60%, and 20% efficacy against R. solani Kuḧn at 200, 100, and 50 μg/mL, respectively. RNA sequence analysis implied that growth inhibition of R. solani by 7k might result from potential disruptions of fungal membrane formation and intracellular metabolism. Furthermore, a field experiment with cucumber plants indicated that 7b showed 62.73% and 74.03% efficacy against Pseudoperonospora cubensis (Berk. & Curt.) Rostov. at rates of 12.5 g a.i./ha and 25 g a.i./ha, respectively, which showed no significant difference between 7b and osthole at 30 g a.i./ha. Our studies suggested that 7b, 7g, and 7k might be used as fungicidal leads for further optimization.
Pyruvate kinase (PK) has been considered as a promising fungicide target discovered in our previous studies. Natural compounds are important sources for discovery and development of new pesticides. To continue our ongoing studies on the discovery of novel PK-targeted fungicides, a series of novel psoralen derivatives including a 1,3,4-oxadiazole moiety were designed by a computer-aided pesticide molecular design method, synthesized, and evaluated for their fungicidal activity. The bioassay results indicated that compounds 11d, 11e, 11g, 11i, and 12a showed excellent in vitro fungicidal activity against Botrytis cinerea with EC 50 values of 4.8, 3.3, 6.3, 5.4, and 3.9 μg/mL, respectively. They were more active than the corresponding positive control YZK ,3,4]-thiadiazole] (with an EC 50 value of 13.4 μg/mL). Compounds 11g and 11i displayed promising in vivo fungicidal activity against B. cinerea with 80 and 70% inhibition at a concentration of 200 μg/mL, respectively. They possessed much higher fungicidal activity than the positive control psoralen and comparable activity with the positive control pyrisoxazole. Enzymatic assays indicated that 11i showed good BcPK inhibition with an IC 50 value of 39.6 μmol/L, comparable to the positive control YZK-C22 (32.4 μmol/L). Molecular docking provided a possible binding mode of 11i in the BcPK active site. Our studies suggested that the psoralen-based 1,3,4-oxadiazole 11i could be used as a new fungicidal lead targeting PK for further structural optimization.
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 IIIf against Mythimna separata showed comparable activity to chloranthraniliprole (LC 50 : 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 IIIf was the most active compound, 25 times more active than chloranthraniliprole (LC 50 : 6.0 × 10 −6 versus 1.5 × 10 −4 mg•L −1 ). For Spodoptera f rugiperda, IIIf displayed slightly inferior potency to chlorantraniliprole (LC 50 : 0.47 versus 0.31 mg•L −1 ). For RyR mutants of S. f rugiperda (G4891E, I4734M), compound IIIf could 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.
To discover novel target-based fungicidal candidates, a molecular design model was established with a threedimensional (3D) structure of Rhizoctonia solani pyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22 as 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 vitro bioassays with R. solani indicated that compounds 5g, 5o, and 5z with an EC 50 value ranging from 1.01 to 1.54 μg/mL displayed higher fungicidal activity than the positive control YZK-C22 with its EC 50 of 3.14 μg/mL. Especially, 5o exhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorum with its EC 50 value falling between 1.54 and 13.10 μg/mL. Like all positive controls, 5g, 5o, and 5z showed excellent in vivo growth inhibition against Pseudoperonospora cubensis at 200 μg/mL. Even though the PK enzymatic inhibition assay showed that 5o was approximately 2.6 times less active than YZK-C22 (IC 50 : 29.14 vs 11.15 μg/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5o and YZK-C22, and the docking results of interactions between RsPK and 5o or YZK-C22 implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5o could 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.
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