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Novel pyrimidine sulfide derivatives containing a dithioacetal and strobilurin moiety were designed and synthesized. Their antiviral activities against tomato chlorosis virus (ToCV) were investigated through the tomato chlorosis virus coat protein (ToCVCP)-oriented screening method. Microscale thermophoresis was used to study the interaction between the compound and the ToCVCP. Compounds B13 and B23 interacted better with ToCVCP than the other compounds and had dissociation constant (K d) values of 0.09 and 0.06 μM, respectively. These values were lower than those of the control agents, ningnanmycin (0.19 μM) and ribavirin (6.54 μM), which indicated that the compounds had a strong binding effect with ToCVCP. Quantitative real-time polymerase chain reaction was used to evaluate the role of compounds B13 and B23 in the gene regulation of ToCVCP. Both compounds significantly reduced the expression level of the ToCVCP gene in Nicotiana benthamiana with reduction values of 88 and 83%, which were better than those of ningnanmycin (65%) and lead compound C14 (73%). Pyrimidine sulfide containing a dithioacetal and strobilurin moiety is significant in the research and development of novel anti-ToCV agents.

A number of novel chromone derivatives containing sulfonamide moieties were designed and synthesized, and the activity of compounds against tomato chlorosis virus (ToCV) was assessed using the ToCVCP-oriented screening method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were established based on the dissociation constant (K d) values of the target compounds, and compound 35 was designed and synthesized with the aid of CoMFA and CoMSIA models. The study of affinity interaction indicated that compound 35 exhibited excellent affinity with ToCVCP with a K d value of 0.11 μM, which was better than that of the positive control agents xiangcaoliusuobingmi (0.44 μM) and ningnanmycin (0.79 μM). In addition, the in vivo inhibitory effect of compound 35 on the ToCVCP gene was evaluated by the quantitative real-time polymerase chain reaction. ToCVCP gene expression levels of the compound 35 treatment group were reduced by 67.2%, which was better than that of the positive control agent ningnanmycin (59.5%). Therefore, compound 35 can be used as a potential anti-ToCV drug in the future.

A series of novel chromone derivatives containing dithioacetals were prepared, and their antiviral activity against tomato spotted wilt virus (TSWV) was studied. The results showed that compounds A1−A31 had good inhibitory activity against TSWV. The 3D-QSAR model was built to analyze the structure−activity relationship of the compounds. We further found that compounds A32 and A33 had excellent anti-TSWV activities based on the results of 3D-QSAR, which were better than the control agents ningnanmycin and ribavirin. To study the mode of action of these compounds on TSWV, the nucleocapsid protein of TSWV (TSWV N) was cloned, expressed, and purified in the study. The results of the microscale thermophoresis (MST) experiments indicate that compound A33 can better bind with TSWV N. The molecular docking experiment further indicated that the mode of action of the compound A33 is to inhibit the virus by blocking the combination of TSWV N and viral RNA. Therefore, this study has found that chromone compound A33 is a potential anti-TSWV agent that targets TSWV N.

Plant immune activators can protect crops from plant virus pathogens by activating intrinsic immune mechanisms in plants and are widely used in agricultural production. In our previous work, we found that curcumin analogs exhibit excellent biological activity against plant viruses, especially protective activity. Inspired by these results, the active substructure of pentadienone and quinazoline were spliced to obtain curcumin analogs as potential exogenously induced resistant molecule. Bioassay results showed that compound A13 exhibited excellent protective activity for tobacco to against Tobacco mosaic virus (TMV) at 500 μg/mL, with a value of 70.4 ± 2.6% compared with control treatments, which was better than that of the plant immune activator chitosan oligosaccharide (49.0 ± 5.9%). The protective activity is due to compound A13 inducing tobacco resistance to TMV, which was related to defense-related enzymes, defense-related genes, and photosynthesis. This was confirmed by the up-regulated expression of proteins that mediate stress responses and oxidative phosphorylation.