Innovative Arylimidazole-Fused Phytovirucides via Carbene-Catalyzed [3+4] Cycloaddition: Locking Viral Cell-To-Cell Movement by Out-Competing Virus Capsid-Host Interactions.

The control of potato virus Y (PVY) induced crop failure is a challengeable issue in agricultural chemistry. Although many anti-PVY agents are designed to focus on the functionally important coat protein (CP) of virus, how these drugs act on CP to inactivate viral pathogenicity, remains largely unknown. Herein, a PVY CP inhibitor -3j (S) is disclosed, which is accessed by developing unusually efficient (up to 99% yield) and chemo-selective (> 99:1 er in most cases) carbene-catalyzed [3+4] cycloaddition reactions. Compound -3j bears a unique arylimidazole-fused diazepine skeleton and shows chirality-preferred performance against PVY. In addition, -3j (S) as a mediator allows ARG191 (R191) of CP to be identified as a key amino acid site responsible for intercellular movement of virions. R191 is further demonstrated to be critical for the interaction between PVY CP and the plant functional protein NtCPIP, enabling virions to cross plasmodesmata. This key step can be significantly inhibited through bonding with the -3j (S) to further impair pathogenic behaviors involving systemic infection and particle assembly. The study reveals the in-depth mechanism of action of antiviral agents targeting PVY CP, and contributes to new drug structures and synthetic strategies for PVY management.

Development and Mechanism Investigation of Novel Thioacetalized Indoles as Antiphytoviral Agents.

Potato virus Y (PVY) is a highly destructive pathogen that infects Solanum tuberosumvL., commonly known as potato, a crop that produces one of the most crucial food staples of the world. The PVY viral infection can considerably reduce the yield and quality of potatoes, thereby causing significant economic ramifications. Given the unsatisfactory performance of commercially available antiviral agents against PVY, we synthesized a series of novel indole-derived compounds followed by their bioevaluation and investigation of the mechanisms governing their anti-PVY activity. These indole-based derivatives contain dithioacetal as a key chemical moiety, and most of them exhibit promising anti-PVY activities. In particular, compound B2 displays remarkable in vivo protective and inactivating properties, with half-maximal effective concentration (EC50) values of 209.3 and 113.0 µg/mL, respectively, in stark contrast to commercial agents such as ningnanmycin (EC50 = 281.4 and 136.3 µg/mL, respectively) and ribavirin (EC50 = 744.8 and 655.4 µg/mL, respectively). The mechanism using which B2 enhances plant immune response to protect plants from PVY is elucidated using enzyme activity tests, real-time quantitative polymerase chain reaction (RT-qPCR), and proteomics techniques. This study aims to pave the way for developing candidate pesticides and related molecules using antiphytoviral activity.

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.

Design, Synthesis, and Anti-PVY Biological Activity of 1,3,5-Triazine Derivatives Containing Piperazine Structure.

In this study, a commercial agent with antivirus activity and moroxydine hydrochloride were employed to perform a lead optimization. A series of 1,3,5-triazine derivatives with piperazine structures were devised and synthesized, and an evaluation of their anti-potato virus Y (PVY) activity revealed that several of the target compounds possessed potent anti-PVY activity. The synthesis of compound C35 was directed by a 3D-quantitative structure-activity relationship that used the compound's structural parameters. The assessment of the anti-PVY activity of compound C35 revealed that its curative, protective, and inactivation activities (53.3 ± 2.5%, 56.9 ± 1.5%, and 85.8 ± 4.4%, respectively) were comparable to the positive control of ningnanmycin (49.1 ± 2.4%, 50.7 ± 4.1%, and 82.3 ± 6.4%) and were superior to moroxydine hydrochloride (36.7 ± 2.7%, 31.4 ± 2.0%, and 57.1 ± 1.8%). In addition, molecular docking demonstrated that C35 can form hydrogen bonds with glutamic acid at position 150 (GLU 150) of PVY CP, providing a partial theoretical basis for the antiviral activity of the target compounds.

Splicing Indoles and 4,5-Dihydro-1H-pyrazoline Structure Gave Birth to Novel Antiviral Agents: Design, Synthesis, and Mechanism Study.

The specific conation of our research is to invent a series of indole derivatives containing a 4,5-dihydro-1H-pyrazoline motif with effective antiviral activity. The anti-potato virus Y (PVY) activities of target compounds were systematically investigated. Most target compounds exhibited good PVY activities. Compound D40, which exhibited outstanding anti-PVY activities, was sieved using a three-dimensional quantitative structure-activity relationship. Based on the anti-PVY activity assessments, the curative and protective activities of D40 were found to be 64.9 and 60.8%, respectively, which were superior to those of the commercial drug Ningnanmycin (50.2 and 50.7%, respectively). In addition, defensive enzyme activities and proteomics results indicate that D40 can increase the three crucial defense-related enzyme activities and regulate the carbon fixation pathway in photosynthetic organisms to intensify the resistance of plants to PVY. Therefore, our study suggests that compound D40 might be used as a suitable crop protection pesticide.

3-Hydroxy-2-oxindole Derivatives Containing Sulfonamide Motif: Synthesis, Antiviral Activity, and Modes of Action.

3-Hydroxy-2-oxindole motif constitutes a core structure in numerous natural products and imparts notable biological activities. Here, we describe the design and synthesis of four series of novel 3-substituted-3-hydroxy-2-oxindole derivatives containing sulfonamide moiety along with their antiviral activities against potato virus Y (PVY). Compound 10b displayed optimal antiviral activity and superior anti-PVY activity compared with the lead compound and commercial Ningnanmycin in terms of curative and protective effects. Additionally, 10b considerably inhibited PVY systemic infection in Nicotiana benthamiana. Physiological and biochemical analyses revealed that the activities of the four crucial defense-related enzymes increased in the tobacco plant following treatment with 10b. RNA-sequencing analysis revealed that 10b substantially induced the upregulation of 38 differentially expressed genes, which were enriched in the photosynthesis pathway. These findings suggest that 10b is a promising antiviral agrochemical that can effectively control PVY infection and trigger plant host immunity to develop virus resistance. This study provides novel molecular entities and ideas for developing new pesticides.

Synthesis, Anti-Potato Virus Y Activities, and Interaction Mechanisms of Novel Quinoxaline Derivatives Bearing Dithioacetal Moiety.

Quinoxaline and its derivatives are important functional molecules with a broad range of applications. Disclosed here is a design and synthesis of a series of novel quinoxaline derivatives containing dithioacetal moieties as well as their antiviral activities against potato virus Y (PVY). The compound D30 was developed on the basis of the three-dimensional quantitative structure-activity relationship. The anti-PVY activity test showed that the half maximal effective concentration of the anti-PVY protective activity of compound D30 is 197 µg/mL, which was better than the control agents ningnanmycin (423 µg/mL) and xiangcaoliusuobingmi (281 µg/mL). Significantly, compound D30 can increase defense enzyme activity and chlorophyll content, promote photosynthesis by accelerating carbon fixation in tobacco, and further improve plant disease resistance. All of these results suggest that compound D30 could be employed as a lead compound for novel PVY inhibitor discovery.

Coumarin Derivatives Containing Sulfonamide and Dithioacetal Moieties: Design, Synthesis, Antiviral Activity, and Mechanism.

Cucumber mosaic virus (CMV) is currently a known plant virus with the most hosts, broadest distribution, and economic hazard. To develop new antiviral drugs against this serious virus, a new range of coumarin derivatives containing sulfonamide and dithioacetal structures were designed and synthesized, and their anti-CMV activities were detected by the half-leaf dead spot method. The results of the biological activity assay showed that most of the compounds exhibited outstanding anti-CMV activity. Especially, compound C23 displayed the optimal in vivo anti-CMV activity, with an EC50 value of 128 µg/mL, which was remarkably better than that of COS (781 µg/mL) and ningnanmycin (436 µg/mL). Excitingly, we found that compound C23 could be a promising plant activator that significantly increased defense-related enzyme activities and the tobacco chlorophyll content. Furthermore, compound C23 enhanced defense responses against viral infection by inducing the abscisic acid (ABA) pathway in tobacco. This work established a basis for multifunction pesticide discovery involving mechanism of action study and structure optimization.

Discovery of novel bis-sulfoxide derivatives bearing acylhydrazone and benzothiazole moieties as potential antibacterial agents.

On the basis of the active substructure combination principle, 24 novel synthesis of novel bis-sulfoxide derivatives bearing acylhydrazone and benzothiazole moieties as potential antibacterial agents were designed and synthesized. The bioactivity assay results showed that many compounds had significant in vitro inhibitory effects against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas citri pv. citri (Xac). Notably, compound 4b had the best in vitro antibacterial activity against Xoo at an half-maximal effective concentration value of 11.4 µg/mL, which was superior to those of thiodiazole copper (TDC) and bismerthiazol (BMT). Compared with TDC and BMT, compound 4b was more effective in vivo controlling rice bacterial leaf blight with curative and protection activities of 42.5% and 40.3%, respectively. In addition, compound 4b can influence biofilm formation, inhibit extracellular polysaccharide production, and ultimately reduce the pathogenicity of Xoo. All the results indicated that bis-sulfoxide derivatives bearing acylhydrazone and benzothiazole moieties can be used for the development of small-molecule pesticides with high antibacterial activity.

Discovery of novel indole derivatives containing dithioacetal as potential antiviral agents for plants.

Thirty unreported indole derivatives containing dithioacetal moiety were synthesized and evaluated for anti-plant viral activity. Bioassay results displayed that some of the target compounds showed better activities against tobacco mosaic virus (TMV) than the commercial Ribavirin in vivo. In particular, anti-TMV curative, protective and inactivating activity of 4p were 55.1, 57.2, and 80.3%, respectively, and EC50 value for inactivating activity was 88.5 µg/mL. The observation of transmission electron microscope showed that 4p may have a certain destructive effect on TMV particles. To further study, microscale thermophoresis analysis result also demonstrated that 4p powerfully interacted with TMV coat protein in vitro. Hence, this study provides a strong evidence suporting that indole derivatives might be applied as new antiviral agents.

Design, Synthesis, and Antiviral Activities of Coumarin Derivatives Containing Dithioacetal Structures.

In this study, a series of coumarin derivatives containing dithioacetals were synthesized, characterized, and assessed for their anti-tobacco mosaic virus (TMV) activities. Biological tests showed that most of the title compounds exhibited significant anti-TMV biological activities; in particular, compound b21 showed good inactivating activity anti-TMV, with an EC50 of 54.2 mg/L, superior to that of ribavirin (134.2 mg/L). Transmission electron microscopy analyses showed that compound 21 severely ruptured TMV particles. The interaction of compound b21 with TMV coat protein (TMV CP) was investigated using microscale thermophoresis and molecular docking. Compound b21 exhibited a strong binding ability to TMV CP, with a value of 2.9 µM, superior to ribavirin.

Synthesis, Antiviral Activity, and Induction of Plant Resistance of Indole Analogues Bearing Dithioacetal Moiety.

A series of compounds with potential activity to induce plant resistance was synthesized from indole and thiol compounds and methodically evaluated for antiviral activity. The results indicated that some of the synthesized compounds had high antipotato virus Y (PVY), anticucumber mosaic virus, and antitobacco mosaic virus activities. Notably, compound D21 exhibited the best activity against PVY among these compounds in vivo, and the 50% effective concentrations (EC50) of protection activity is 122 µg/mL, which was distinctively better than the corresponding values for ribavirin (653 µg/mL), Ningnanmycin (464 µg/mL), and Xiangcaoliusuobingmi (279 µg/mL). Interestingly, we found that the protection activity of D21 was associated with improvement of chlorophyll content and defense-related enzyme activities. Moreover, D21 could trigger the malate dehydrogenase (MDH) signaling pathway, as further confirmed by the MDH activity evaluation. Hence, D21 can protect plants against viral activity and has potential as a novel activator for plant resistance induction.