Aminated Quinolinequinones as Privileged Scaffolds for Antibacterial Agents: Synthesis, In Vitro Evaluation, and Putative Mode of Action.

Our previous studies have revealed that the aminated 1,4-quinone scaffold can be used for the development of novel antibacterial and/or antifungal agents. In this study, the aminated quinolinequinones ( AQQ1-9 ) were designed, synthesized, and evaluated for their antimicrobial activity against a panel of seven bacterial strains (three Gram-positive and four Gram-negative bacteria) and three fungal strains. The structure-activity relationship (SAR) for the QQs was also summarized. The antibacterial activity results indicated that the two aminated QQs ( AQQ6 and AQQ9 ) were active against Enterococcus faecalis (ATCC 29212) with a MIC value of 78.12 μg/mL. Besides, the two aminated QQs ( AQQ8 and AQQ9 ) were active against Staphylococcus aureus (ATCC 29213) with MIC values of 4.88 and 2.44 μg/mL, respectively. The most potent aminated QQs ( AQQ8 and AQQ9 ) were identified as promising lead molecules to further explore their mode of action. The selected QQs ( AQQ8 and AQQ9 ) were further evaluated in vitro to assess their potential antimicrobial activity against each of 20 clinically obtained methicillin-resistant S. aureus isolates, antibiofilm activity, and bactericidal activity using time-kill curve assay. We found that the molecules prevented adhesion of over 50% of the cells in the biofilm. Molecular docking studies were performed to predict the predominant binding mode(s) of the ligands. We believe that the molecules need further investigation, especially against infections involving biofilm-forming microbes.