Evaluation of 1,4-naphthoquinone derivatives as antibacterial agents: activity and mechanistic studies

Highlights

● All 1,4-naphthoquinone hybrids exhibited significant antimicrobial activity.

● Presence of a hydroxyl group on aromatic B-ring of juglone was crucial for activity.

● Juglone can cause DNA damage by producing ROS and downregulation of RecA.

● Juglone has the potential to become a disinfectant.

Abstract

The diverse and large-scale application of disinfectants posed potential health risks and caused ecological damage during the 2019-nCoV pandemic, thereby increasing the demands for the development of disinfectants based on natural products, with low health risks and low aquatic toxicity. In the present study, a few natural naphthoquinones and their derivatives bearing the 1,4-naphthoquinone skeleton were synthesized, and their antibacterial activity against selected bacterial strains was evaluated. In vitro antibacterial activities of the compounds were investigated against Escherichia coli and Staphylococcus aureus. Under the minimum inhibitory concentration (MIC) of ≤ 0.125 μmol/L for juglone (1a), 5,8-dimethoxy-1,4-naphthoquinone (1f), and 7-methyl-5-acetoxy-1,4-naphthoquinone (3c), a strong antibacterial activity against S. aureus was observed. All 1,4-naphthoquinone derivatives exhibited a strong antibacterial activity, with MIC values ranging between 15.625 and 500 μmol/L and EC₅₀ values ranging between 10.56 and 248.42 μmol/L. Most of the synthesized compounds exhibited strong antibacterial activities against S. aureus. Among these compounds, juglone (1a) showed the strongest antibacterial activity. The results from mechanistic investigations indicated that juglone, a natural naphthoquinone, caused cell death by inducing reactive oxygen species production in bacterial cells, leading to DNA damage. In addition, juglone could reduce the self-repair ability of bacterial DNA by inhibiting RecA expression. In addition to having a potent antibacterial activity, juglone exhibited low cytotoxicity in cell-based investigations. In conclusion, juglone is a strong antibacterial agent with low toxicity, indicating that its application as a bactericidal agent may be associated with low health risks and aquatic toxicity.

Graphical abstract

Keywords

1, 4-naphthoquinone derivatives / Antibacterial / Action mechanism / RecA

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Acknowledgements

This work was co-supported by the Startup Fund for Youngman Research at SJTU (No. 19X100040082) and the Medical and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University (No. 20X190020002).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11783-023-1631-2 and is accessible for authorized users.

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