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Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G^&#8722;) bacteria, taking compound <b>1</b> as the lead. Among the target compounds, quinolone coupled hybrid <b>5d</b> exerted the potential effect against most of the tested G⁺ and G^&#8722; strains with MIC values of 0.125&#8315;8 &#956;g/mL, much better than those of <b>1</b>. Molecular-docking assay showed that compound <b>5d</b> might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound <b>5d</b> was selected for the further investigation, with an advantage of a dual-target mechanism of action.