Engineering Phenothiazine-Based Functional Mimics of Host Defense Peptides as New Agrochemical Candidates: Design, Synthesis, and Antibacterial Evaluation.

In the protracted "arms race" between host and plant pathogenic bacteria, host organisms have evolved powerful weapons known as host defense peptides (HDPs). However, natural HDPs are not suitable for large-scale applications; therefore, researchers have chosen to develop bespoke small-molecule functional mimics. Phenothiazine derivatives were developed as functional HDPs mimics, owing to their broad biological activity and high lipophilicity. The phenothiazine analogues designed in this study exhibited excellent in vitro bioactivity against the three Gram-negative bacteria Xanthomonas oryzae pv oryzae, Xanthomonas axonopodis pv citri, and Pseudomonas syringae pv actinidiae, with optimal EC50 values of 0.80, 0.31, and 1.91 µg/mL, respectively. Preliminary evidence suggests that compound C2 may act on bacterial cell membranes and interact with bacterial Deoxyribonucleic acid in the groove binding mode. In vivo trials showed that compound C2 was highly effective against rice leaf blight (51.97-56.69%), with activity superior to those of bismerthiazol (40.7-43.4%) and thiodiazole copper (30.2-37.1%). Our study provides strong evidence to support the development of phenothiazine derivatives into pesticide candidates.

Discovery of novel phenothiazine derivatives as new agrochemical alternatives for treating plant viral diseases.

BACKGROUND: Plant viral diseases, namely 'plant cancer', are extremely difficult to control. Even worse, few antiviral agents can effectively control and totally block viral infection. There is an urgent need to explore and discover novel agrochemicals with high activity and a unique mode of action to manage these refractory diseases. RESULTS: Forty-one new phenothiazine derivatives were prepared and their inhibitory activity against tobacco mosaic virus (TMV) was assessed. Compound A8 had the highest protective activity against TMV, with a half-maximal effective concentration (EC50 ) of 115.67 µg/mL, which was significantly better than that of the positive controls ningnanmycin (271.28 µg/mL) and ribavirin (557.47 µg/mL). Biochemical assays demonstrated that compound A8 could inhibit TMV replication by disrupting TMV self-assembly, but also enabled the tobacco plant to enhance its defense potency by increasing the activities of various defense enzymes. CONCLUSION: In this study, novel phenothiazine derivatives were elaborately fabricated and showed remarkable anti-TMV behavior that possessed the dual-action mechanisms of inhibiting TMV assembly and invoking the defense responses of tobacco plants. Moreover, new agrochemical alternatives based on phenothiazine were assessed for their antiviral activities and showed extended agricultural application. © 2023 Society of Chemical Industry.

Novel Benzothiazole Derivatives as Potential Anti-Quorum Sensing Agents for Managing Plant Bacterial Diseases: Synthesis, Antibacterial Activity Assessment, and SAR Study.

As quorum sensing (QS) regulates bacterial pathogenicity, antiquorum sensing agents have powerful application potential for controlling bacterial infections and overcoming pesticide/drug resistance. Identifying anti-QS agents thus represents a promising approach in agrochemical development. In this study, the anti-QS potency of 53 newly prepared benzothiazole derivatives containing an isopropanolamine moiety was analyzed, and structure-activity relationships were examined. Compound D3 exhibited the strongest antibacterial activity, with an in vitro EC50 of 1.54 µg mL-1 against Xanthomonas oryzae pv oryzae (Xoo). Compound D3 suppressed QS-regulated virulence factors (e.g., biofilm, extracellular polysaccharides, extracellular enzymes, and flagella) to inhibit bacterial infection. In vivo anti-Xoo assays indicated good control efficiency (curative activity, 47.8%; protective activity, 48.7%) at 200 µg mL-1. Greater control efficiency was achieved with addition of 0.1% organic silicone or orange peel essential oil. The remarkable anti-QS potency of these benzothiazole derivatives could facilitate further novel bactericidal compound development.

Exploiting Natural Maltol for Synthesis of Novel Hydroxypyridone Derivatives as Promising Anti-Virulence Agents in Bactericides Discovery.

Anti-infection strategies based on suppression of bacterial virulence factors represent a crucial direction for the development of new antibacterial agents to address the resistance triggered by traditional drugs'/pesticides' bactericidal activity. To identify and obtain more effective and diverse molecules targeting virulence, we prepared a series of 3-hydroxy-2-methyl-1-pyridin-4-(1H)-one derivatives and evaluated their antibacterial behaviors. Compound B6 exhibited the highest bioactivity, with half-maximal effective concentration (EC50) values ranging fro9m 10.03 to 30.16 µg mL-1 against three plant pathogenic bacteria. The antibacterial mechanism showed that it could considerably reduce various virulence factors (such as extracellular enzymes, biofilm, and T3SS effectors) and inhibit the expression of virulence factor-related genes. In addition, the control efficiency of compound B6 against rice bacterial leaf blight at 200 µg mL-1 was 46.15-49.15%, and their control efficiency was improved by approximately 12% after the addition of pesticide additives. Thus, a new class of bactericidal candidates targeting bacterial virulence factors was developed for controlling plant bacterial diseases.

Resistance-driven innovations in the discovery of bactericides: novel triclosan derivatives decorating isopropanolamine moiety as promising anti-biofilm agents against destructive plant bacterial diseases.

BACKGROUND: Controlling bacterial infections in plants is a major challenge owing to the appearance of resistant strains. As a physical barrier, the bacterial biofilm helps bacterial infections acquire drug resistance by enabling bacteria to accommodate complex and volatile environmental conditions and avoid bactericidal effects. Thus, developing new antibacterial agents with antibiofilm potency is imperative. RESULTS: A series of simple triclosan derivatives containing isopropanolamine moiety were elaborately designed and assessed for their antibacterial behavior. Bioassay results showed that some title compounds had excellent bioactivity against three destructive bacteria Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac) and Pseudomonas syringae pv. actinidiae (Psa). Notably, compound C8 displayed high bioactivities toward Xoo and Xac, with EC50 values were 0.34 and 2.11 µg mL-1 , respectively. In vivo trials revealed that compound C8 exhibited excellent protective activities against rice bacterial blight and citrus bacterial canker at 200 µg mL-1 , with control effectivenesses of 49.57% and 85.60%, respectively. Compound A4 had remarkably inhibitory activity toward Psa, with an EC50 value of 2.63 µg mL-1 , and demonstrated outstanding protective activity with a value of 77.23% against Psa in vivo. Antibacterial mechanisms indicated that compound C8 dose-dependently prevented biofilm formation and extracellular polysaccharide production. C8 also significantly weakened the motility and pathogenicity of Xoo. CONCLUSION: This study contributes to the development and excavation of novel bactericidal candidates with broad-spectrum antibacterial activity by targeting bacterial biofilm to control refractory plant bacterial diseases. © 2023 Society of Chemical Industry.

Fabrication of Isopropanolamine-Decorated Coumarin Derivatives as Novel Quorum Sensing Inhibitors to Suppress Plant Bacterial Disease.

Emerging pesticide-resistant phytopathogenic bacteria have become a stumbling block in the development and use of pesticides. Quorum sensing (QS) blockers, which interfere with bacterial virulence gene expression, are a compelling way to manage plant bacterial disease without resistance. Herein, a series of isopropanolamine-decorated coumarin derivatives were designed and synthesized, and their potency in interfering with QS was investigated. Notably, compound A5 exhibited a better bioactivity with median effective concentration (EC50) values of 6.75 mg L-1 against Xanthomonas oryzae pv. oryzae (Xoo) than bismerthiazol (EC50 = 21.9 mg L-1). Further biochemical studies revealed that compound A5 disturbed biofilm formation and suppressed bacterial virulence factors and so forth. Moreover, compound A5 decreased the expression of QS-related genes. Interestingly, compound A5 had the acceptable control effect (53.2%) toward Xoo in vivo. Overall, this study identifies a novel lead compound for the development of bactericide candidates to control plant bacterial diseases by interfering with QS.