To develop novel antibacterial agents, 2-sulfoether-4-quinolone scaffolds were synthesized by a free radical process and evaluated for their antibacterial abilities. Excellent activities against Gram-positive bacteria were observed, among which compounds 3m, 3n, 3p and 3t possessed the lowest MICs against both S. aureus and B. cereus (0.8 μM and 1.61 μM, respectively). The structure-activity relationship (SAR) showed that: (i) the antibacterial activity was related to the substituent, such as 2-SCH3 = 2-SCH2CH3 > 2-S(=O)CH3 > 2-OH, 8-Br > 7-Br > 6-Br; (ii) -CF3 increased the antibacterial activity; (iii) the di-substituted group performed the better activity. The DNA supercoiling inhibitory analysis confirmed their fluoroquinolone characters. The docking showed that compound 3n was nicely bound into the DNA-gryase complex via extensive interactions, including conventional hydrogen bonds, halogen bonds and hydrophobic interactions. The microscopy analysis of compound 3n against S. aureus exhibited the damages on the cell wall construction, which may facilitate the penetration into Gram-positive bacteria.
Keywords: Antibacterial; DNA gyrase; Electron microscope; Free radical process; Quinolone.
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