Structural optimization of SDH-targeting chalcone derivatives: piperazine-driven binding stability against...

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.

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 (EC₅₀) value of 3.25 μg mL^-1 against Xcm, significantly surpassing the commercial agent (TC, EC₅₀ = 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.

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.