Structural optimization of SDH ‐targeting chalcone derivatives: piperazine‐driven binding stability against Xanthomonas pathogens

Abstract BACKGROUND Natural green pesticides have become a global research hotspot, and identifying chemical structural frameworks with excellent biological activity has become the research direction of numerous researchers. RESULTS Twenty chalcone derivatives incorporating 1,2,3,4‐tetrahydroquinoline scaffolds were systematically evaluated for their antibacterial activity against six plant pathogenic bacteria. Among the tested compounds, H1–H10 exhibited superior in vitro inhibition against Xanthomonas citri pv. mangiferaeindicae ( Xcm ) compared to Y1–Y10. Notably, compound H6 demonstrated exceptional potency, with a median effective concentration (EC 50 ) value of 3.25 μg mL −1 against Xcm , significantly surpassing the commercial agent (TC, EC 50  = 75.34 μg mL −1 ). In vivo efficacy trials revealed that H6 achieved 65.24% curative activity at 100 μg mL −1 , outperforming TC (42.81%). Scanning electron microscopy further confirmed H6's disruptive effects on bacterial membrane integrity. Mechanistic studies targeting succinate dehydrogenase (SDH), a key respiratory enzyme, revealed structural and energetic similarities between H6 and the commercial SDH inhibitor bixafen through molecular docking and dynamics simulations. CONCLUSION The 1,2,3,4‐tetrahydroquinoline moiety enhanced SDH binding affinity, while the introduced piperazine substructure in H6 improved both complex stability (root mean square deviation <1.5 Å) and target engagement. These findings establish H6 as a promising lead compound for developing next‐generation SDH inhibitors, providing critical insights into structure–activity relationships for agricultural antimicrobial design. © 2025 Society of Chemical Industry.