Identification of acylhydrazone derivatives with isopropanolamine moiety as potent anti‐virulence agents for combating bacterial infection

BACKGROUND Quorum sensing (QS)‐regulated virulence factors including biofilms are key drivers of phytopathogen pathogenicity and antimicrobial resistance. Unlike conventional bactericides that exert selective pressure leading to resistance evolution, anti‐virulence agents offer a promising strategy to control bacterial diseases without promoting resistance, having significant potential in the creation of new bactericides. RESULTS In this study, hydroxybenzaldehyde was used as the starting material to synthesize a series of 39 novel acylhydrazone derivatives containing flexible isopropanolamine moieties. Among these, compound C19 exhibited excellent in vitro activity against the rice bacterial blight pathogens Xanthomonas oryzae pv. oryzae ( Xoo ) and Xanthomonas axonopodis pv. citri ( Xac ), with in vitro EC 50 (Half maximal effective concentration) values of 1.66 μg/mL and 1.19 μg/mL, respectively—significantly outperforming commercial bactericides bismerthiazol (BT EC 50 = 45.74 μg/mL for Xoo ; 51.23 μg/mL for Xac ) and thiodiazole‐copper (TC EC 50 = 108.10 μg/mL for Xoo ; 81.54 μg/mL for Xac ). At a concentration of 200 μg/mL, compound C19 showed protective and curative efficacies of 47.3% and 46.2%, respectively, both of which were superior to those of the commercial bactericides BT (44.3% and 44.5%) and TC (43.8% and 42.5%). Mechanistically, compound C19 effectively inhibited Xoo biofilm formation, bacterial motility and extracellular enzyme secretion, thereby reducing pathogen virulence and thus suppressing the bacterial infection process. CONCLUSION This study successfully designed and synthesized a series of novel isopropanolamine‐modified acylhydrazone derivatives as potent anti‐virulence agents. Compound C19 , with its excellent antibacterial activity, favorable safety profile and unique anti‐virulence performance, represents a promising lead compound for the development of novel environmentally friendly bactericides to combat bacterial resistance.