Targeting the virulence factors of phytopathogenic bacteria is an innovative strategy for alleviating or eliminating the pathogenicity and rapid outbreak of plant microbial diseases. Therefore, several types of 1,2,4-triazole thioethers bearing an amide linkage were prepared and screened to develop virulence factor inhibitors. Besides, the 1,2,4-triazole scaffold was exchanged by a versatile 1,3,4-oxadiazole core to expand molecular diversity. Bioassay results revealed that a 1,2,4-triazole thioether A 10 bearing a privileged N-(3-nitrophenyl)­acetamide fragment was extremely bioactive against Xanthomonas oryzae pv. oryzae (Xoo) with an EC50 value of 5.01 μg/mL. Label-free quantitative proteomics found that compound A 10 could significantly downregulate the expression of Xoo’s type III secretion system (T3SS) and transcription activator-like effector (TALE) correlative proteins. Meanwhile, qRT-PCR detection revealed that the corresponding gene transcription levels of these virulence factor-associated proteins were substantially inhibited after being triggered by compound A 10 . As a result, the hypersensitive response and pathogenicity were strongly depressed, indicating that a novel virulence factor inhibitor (A 10 ) was probably discovered. In vivo anti-Xoo trials displayed that compound A 10 yielded practicable control efficiency (54.2–59.6%), which was superior to thiadiazole-copper and bismerthiazol (38.1–44.9%). Additionally, compound A 10 showed an appreciable antiviral activity toward tobacco mosaic virus (TMV) with the curative and protective activities of 54.6 and 76.4%, respectively, which were comparable to ningnanmycin (55.2 and 60.9%). This effect was further validated and visualized by the inoculation test using GFP-labeled TMV, thereby leading to the reduced biosynthesis of green-fluorescent TMV on Nicotiana benthamiana. Given the outstanding features of compound A 10 , it should be deeply developed as a versatile agricultural chemical.

Target-based drug design, a high-efficiency strategy used to guide the development of novel pesticide candidates, has attracted widespread attention. Herein, various natural-derived ferulic acid derivatives incorporating substituted isopropanolamine moieties were designed to target the tobacco mosaic virus (TMV) helicase. Bioassays demonstrating the optimized A19, A20, A29, and A31 displayed excellent in vivo antiviral curative abilities, affording corresponding EC50 values of 251.1, 336.2, 347.1, and 385.5 μg/mL, which visibly surpassed those of commercial ribavirin (655.0 μg/mL). Moreover, configurational analysis shows that the R-forms of target compounds were more beneficial to aggrandize antiviral profiles. Mechanism studies indicate that R-A19 had a strong affinity (Kd = 5.4 μM) to the TMV helicase and inhibited its ability to hydrolyze ATP (50.61% at 200 μM). Meanwhile, A19 could down-regulate the expression of the TMV helicase gene in the host to attenuate viral replication. These results illustrate the excellent inhibitory activity of A19 towards the TMV helicase. Additionally, docking simulations uncovered that R-A19 formed more hydrogen bonds with the TMV helicase in the binding pocket. Recent studies have unambiguously manifested that these designed derivatives could be considered as promising potential helicase-based inhibitors for plant disease control.

BackgroundThe discovery and identification of targets is of far‐reaching significance for developing novel pesticide candidates and increasing the probability of success. To explore and identify highly effective tobacco mosaic virus (TMV) helicase‐targeted lead structures, a series of novel phosphonate derivatives containing a 1,2,3‐triazole motif were rationally engineered and their antiviral activity was assessed.ResultsBioassay results showed that the optimized B17 exhibited more potent curative activity (EC50 = 271.5 μg mL−1) against TMV in vivo, which was superior to that of commercial Ribavirin (EC50 = 689.3 μg mL−1). B17 presented a stronger binding capacity through binding analysis with helicase, affording a corresponding value of 12.7 μM. Enzyme activity assay showed B17 exhibited excellent inhibitory activity on TMV helicase (39.2% at 300 μM). Furthermore, molecular docking simulations demonstrated that B17 displayed strong hydrogen‐bond interactions (2.1, 2.1, 2.2, and 3.2 Å) with Ala‐33, Gly‐10, Gly‐8, and Glu‐217 of TMV helicase. Encouragingly, transmission electron microscopy analysis revealed that B17 could remarkably disrupt surface morphology and inhibit TMV proliferation. Additionally, these compounds also displayed potential anti‐CMV (cucumber mosaic virus) and antipathogens (Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri) by expanding their applications in agriculture.ConclusionCurrent research demonstrated that B17 could be considered as a potential antiviral agent alternative though targeting TMV helicase. © 2023 Society of Chemical Industry.

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