The emergence of pathogenic multidrug-resistant bacteria demands new approaches in finding effective antibacterial agents. Synthetic flavonoids could be a reliable solution due to their important antimicrobial activity. We report here the potent in vitro antibacterial activity of ClCl-flav—a novel synthetic tricyclic flavonoid. The antimicrobial effects were tested using the minimum inhibitory concentration (MIC), time kill and biofilm formation assays. Fluorescence microscopy and scanning electron microscopy were employed to study the mechanism of action. MTT test was used to assess the cytotoxicity of ClCl-flav. Our results showed that Gram positive bacteria were more sensitive (MIC = 0.24 μg/mL) to ClCl-flav compared to the Gram negative ones (MIC = 3.9 μg/mL). We found that our compound showed significantly enhanced antibacterial activities, 32 to 72-fold more active than other synthetic flavonoids. ClCl-flav showed bactericidal activity at concentrations ranging from 0.48 to 15.62 μg/mL. At twice the MIC, all Escherichia coli and Klebsiella pneumoniae cells were killed within 1 h. Also ClCl-flav presented good anti-biofilm activity. The mechanism of action is related to the impairment of the cell membrane integrity. No or very low cytotoxicity was evidenced at effective concentrations against Vero cells. Based on the strong antibacterial activity and cytotoxicity assessment, ClCl-flav has a good potential for the design of new antimicrobial agents.

Based on the strong antimicrobial activity observed, this new tricyclic flavonoid has a good potential for the design of new antimicrobial agents.

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The emergence of drug-resistant microbes left us with a great need for new antimicrobial agents. Flavonoids, with their wide range of biological activities, are good candidates in this respect. Although naturally occurring flavonoids are the most studied ones, semi-synthetic or synthetic flavonoids have proven to have great potential, inhibiting and even killing microbes at concentrations below 1 lg ml À1 . The substitution pattern of these flavonoids often includes hydroxy groups, halogens or other heteroatomic rings, such as pyridine, piperidine or 1,3-dithiolium cations. However, the great variety in substituents makes it difficult to draw any definitive conclusion regarding their structureactivity relationship.

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