Novel cationic pyridine-phenylamide compounds: design, synthesis, and mechanism of action as antibacterial agents.

BACKGROUND: Plant bacterial diseases caused by Xanthomonas oryzae pv. oryzicola (Xoc) and Xanthomonas axonopodis pv. citri (Xac) cause severe yield losses, and increasing resistance to existing bactericides demands novel antibacterial agents. Guided by a molecular hybridization and cationization strategy, a series of pyridine-phenylamide derivatives and their cationic N-alkylpyridinium analogs were designed and synthesized. RESULTS: Bioassay demonstrated that cationic functionalization drastically enhanced antibacterial potency. Compound B6 emerged as the most potent candidate, with median effective concentration values of 0.70 μg/mL against Xoc and 1.33 μg/mL against Xac, representing 77-fold and 46.7-fold improvements over bismerthiazol, respectively. In vivo trials confirmed that B6 provided significant protective and curative efficacy in rice. Mechanistic studies revealed that B6 not only inhibited biofilm formation and extracellular polysaccharide production but also activated rice immune responses via induction of defense enzymes (peroxidase, phenylalanine ammonia-lyase, superoxide dismutase, and polyphenol oxidase) and systemic transcriptional reprogramming. CONCLUSION: Compound B6 represents a promising dual-action antibacterial lead that combines direct pathogen inhibition with host immune activation. This study validates cationic functionalization as a powerful strategy for developing next-generation agrochemicals with reduced resistance risk. © 2026 Society of Chemical Industry.