Toxicokinetics, Tissue Distribution, and Excretion of Dufulin Racemate and Its <i>R</i> (<i>S</i>)‑Enantiomers in Rats

Dufulin is a plant antiviral agent with a novel molecular structure and has been used widely to prevent and control tobacco and rice viral diseases. In this study, an UHPLC-MS/MS method was developed for rapid determination of dufulin racemate (rac-DFL) and its R (S)-enantiomers in rat plasma, tissues, urine, and feces. A MALDI-MSI method was further used for visual research on tissue distribution after intragastric administration of the three analytes. Toxicokinetic study showed that both (R)-enantiomer of dufulin ((R)-DFL) and (S)-enantiomer of dufulin ((S)-DFL) had a faster ability to reach Cmax than that of rac-DFL. (R)-DFL and (S)-DFL had a similar T1/2, though both were significantly lower than rac-DFL. Cmax of rac-DFL was obviously higher than (R)-DFL or (S)-DFL. Meanwhile, Cmax of (S)-DFL was only about 60% of (R)-DFL. Rac-DFL and its R (S)-enantiomers had a dose-dependent toxicokinetic profile. Tissue distribution results revealed rac-DFL, (R)-DFL, and (S)-DFL mainly distributed in the liver and kidney, but the maximum concentration was only ng/g grade and could significantly degrade within 3 h. This indicates that dufulin does not cause liver and kidney toxicity in animals. In addition, rac-DFL and its R (S)-enantiomers have not been detected in brain tissue. Cumulative excretion of rac-DFL and its R (S)-enantiomers within 24 h in urine and feces were less than 22.85% indicating that they mainly excreted as metabolites. These results could provide evidence for the in-depth toxicity evaluation of dufulin pesticide. In addition, its metabolic selectivity information in vivo has also been obtained

Design, Synthesis, Anti-Tomato Spotted Wilt Virus Activity, and Mechanism of Action of Thienopyrimidine-Containing Dithioacetal Derivatives

Currently, there is insufficient viricide to effectively control tomato spotted wilt virus (TSWV). To address this pending issue, a series of thienopyrimidine-containing dithioacetal derivatives were prepared and tested for their anti-TSWV activities. A subsequent three-dimensional quantitative structure–activity relationship was constructed to indicate the development of optimal compound 35. The obtained compound 35 had excellent anti-TSWV curative, protective, and inactivating activities (63.0, 56.6, and 74.1%, respectively), and the EC50 values of protective and inactivating activities of compound 35 were 252.8 and 113.5 mg/L, respectively, better than those of ningnanmycin (284.8 and 144.7 mg/L) and xiangcaoliusuobingmi (624.9 and 300.0 mg/L). In addition, the anti-TSWV activity of compound 35 was associated with defense-related enzyme activities, enhanced photosynthesis, and reduced stress response, thereby enhancing disease resistance

Defense Mechanism of Capsicum annuum L. Infected with Pepper Mild Mottle Virus Induced by Vanisulfane

Pepper mild mottle virus (PMMoV), an RNA virus, is one of the most devastating pathogens in pepper crops and has a significant influence on global crop yields. PMMoV poses a major threat to the global shortage of pepper plants and other Solanaceae crops due to the lack of an effective antiviral agent. In this study, we have developed a plant immune inducer (vanisulfane), as a “plant vaccine” that boosts plant immunity against PMMoV, and studied its resistance mechanism. The protective activity of vanisulfane against PMMoV was 59.4%. Vanisulfane can enhance the activity of defense enzymes and improve the content of chlorophyll, flavonoids, and total phenols for removing harmful free radicals from plants. Furthermore, vanisulfane was found to enhance defense genes. Label-free quantitative proteomics would tackle disease resistance pathways of vanisulfane. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, differentially abundant proteins (DAPs) are mainly involved in starch and sucrose metabolism, photosynthesis, MAPK signaling pathway, and oxidative phosphorylation pathway. These results are crucial for the discovery of new pesticides, understanding the improvement of plant immunity and the antiviral activity of plant immune inducers

Design, Synthesis, Anti-Tomato Spotted Wilt Virus Activity, and Mechanism of Action of Thienopyrimidine-Containing Dithioacetal Derivatives

Currently, there is insufficient viricide to effectively control tomato spotted wilt virus (TSWV). To address this pending issue, a series of thienopyrimidine-containing dithioacetal derivatives were prepared and tested for their anti-TSWV activities. A subsequent three-dimensional quantitative structure–activity relationship was constructed to indicate the development of optimal compound 35. The obtained compound 35 had excellent anti-TSWV curative, protective, and inactivating activities (63.0, 56.6, and 74.1%, respectively), and the EC50 values of protective and inactivating activities of compound 35 were 252.8 and 113.5 mg/L, respectively, better than those of ningnanmycin (284.8 and 144.7 mg/L) and xiangcaoliusuobingmi (624.9 and 300.0 mg/L). In addition, the anti-TSWV activity of compound 35 was associated with defense-related enzyme activities, enhanced photosynthesis, and reduced stress response, thereby enhancing disease resistance

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Diacylhydrazine Compounds as GABA Receptor Inhibitors

A series of isoxazoline derivatives containing diacylhydrazine moieties were designed and synthesized as potential insecticides. Most of these derivatives exhibited good insecticidal activities against Plutella xylostella, and some compounds exhibited excellent insecticidal activities against Spodoptera frugiperda. Especially, D14 showed outstanding insecticidal activity against P. xylostella (LC50 = 0.37 μg/mL), which was superior to that of ethiprole (LC50 = 2.84 μg/mL) and tebufenozide (LC50 = 15.3 μg/mL) and similar to that of fluxametamide (LC50 = 0.30 μg/mL). Remarkably, the insecticidal activity of D14 against S. frugiperda (LC50 = 1.72 μg/mL) was superior to that of chlorantraniliprole (LC50 = 3.64 μg/mL) and tebufenozide (LC50 = 60.5 μg/mL) but lower than that of fluxametamide (LC50 = 0.14 μg/mL). The results of electrophysiological experiments, molecular docking, and proteomics experiments indicate that compound D14 acts by interfering with the γ-aminobutyric acid receptor to control pests

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Diacylhydrazine Compounds as GABA Receptor Inhibitors

A series of isoxazoline derivatives containing diacylhydrazine moieties were designed and synthesized as potential insecticides. Most of these derivatives exhibited good insecticidal activities against Plutella xylostella, and some compounds exhibited excellent insecticidal activities against Spodoptera frugiperda. Especially, D14 showed outstanding insecticidal activity against P. xylostella (LC50 = 0.37 μg/mL), which was superior to that of ethiprole (LC50 = 2.84 μg/mL) and tebufenozide (LC50 = 15.3 μg/mL) and similar to that of fluxametamide (LC50 = 0.30 μg/mL). Remarkably, the insecticidal activity of D14 against S. frugiperda (LC50 = 1.72 μg/mL) was superior to that of chlorantraniliprole (LC50 = 3.64 μg/mL) and tebufenozide (LC50 = 60.5 μg/mL) but lower than that of fluxametamide (LC50 = 0.14 μg/mL). The results of electrophysiological experiments, molecular docking, and proteomics experiments indicate that compound D14 acts by interfering with the γ-aminobutyric acid receptor to control pests

Synthesis, Anti-Tomato Spotted Wilt Virus Activities, and Interaction Mechanisms of Novel Dithioacetal Derivatives Containing a 4(3<i>H</i>)‑Quinazolinone Pyrimidine Ring

A series of unreported novel dithioacetal derivatives containing a 4­(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC50 values of 144 μg/mL, which was better than those of ningnanmycin (149 μg/mL) and the lead compound xiangcaoliusuobingmi (525 μg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 μM, which was better than those of ningnanmycin (6.2 μM) and xiangcaoliusuobingmi (59.1 μM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4­(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents

Vanisulfane Induced Plant Resistance toward Potato Virus Y via the Salicylic-Depended Acid Signaling Pathway

Vanisulfane is a plant resistance inducer that exhibits potent activity against potato virus Y (PVY), but its mechanism of action against this virus remains unclear. Our results showed that when we used 400 μg/mL of vanisulfane, it provided an impressive level of control (63.55%) against PVY in Nicotiana benthamiana L. Meanwhile, vanisulfane increased activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and phenylalanine ammonia lyase (PAL) as well as inducing H2O2 accumulation and Ca2+ influx to mediate PVY resistance. Furthermore, combined transcriptome and proteome analyses revealed that vanisulfane upregulated the POD52, APX, and PR-1 genes and proteins in the salicylic acid (SA) signaling pathway. Experiments demonstrated that vanisulfane triggered the accumulation of SA, upregulated the expression of ICS1 and PR-1 genes, and induced resistance against PVY in transgenic Arabidopsis plants. Consequently, it can be concluded that vanisulfane mediates the SA-dependent signaling pathway to confer PVY resistance in plants

Synthesis and Antibacterial Activities of 2-<i>Oxo</i>-<i>N</i>‑phenylacetamide Derivatives Containing a Dissulfone Moiety Target on Clp

Rice bacterial blight and rice bacterial streak are two serious rice diseases and have caused great harm to the production of rice all over the world. To develop an efficient antibacterial agent with a novel target, a series of novel 2-oxo-N-phenylacetamide derivatives containing a dissulfone moiety were synthesized, and their antibacterial activities were evaluated. Among them, compound D14 exhibited the best antibacterial activities, especially against Xoo and Xoc with EC50 values of 0.63 and 0.79 mg/L, respectively, which were much better than the commercial control of bismerthiazol (BT) (76.59 and 83.35 mg/L, respectively) and thiodiazole copper (TC) (91.72 and 114.00 mg/L, respectively). Meanwhile, compound D14 can interact with a CRP-like protein (Clp) of Pxo99A and show strong binding activity with Xoo-Clp with a Kd value of 0.52 μM, which was far superior to the corresponding Kd values of BT (183.94 μM) and TC (222.58 μM). Treatment of D14 and deletion of the clp gene could significantly reduce the expression of the clp gene and attenuate the virulence of pathogenic bacteria. These results indicated that compound D14 could be used as a potential novel agricultural bactericide and Clp can be used as a target protein for the control of plant bacterial diseases. This work provided reliable support for developing novel antibacterial agents based on Clp as a target protein