Membrane-active substituted triazines as antibacterial agents against Staphylococcus aureus with potential for low drug resistance and broad activity

A library of new naphthalimide-triazine analogues was synthesized as broad-spectrum Antibacterial agents to overcome drug resistance. Bioactivity assay reveals that derivative 8e, with benzylamine in its structure, exhibits strong Antibacterial properties against multi-drug resistance Staphylococcus aureus at a concentration of 1.56 μg/ml. It was also found to be better than chloromycin and amoxicillin. The active compound 8e efficiently inhibits the development of drug resistance within 11 passages. In addition, compound 8e inhibits the formation of biofilms in S. aureus and acts rapidly in bactericidal efficacy. Furthermore, mechanistic studies reveal that compound 8e effectively destroys the cytoplasmic membrane of bacteria, leading to leakage of intercellular protein content and loss in metabolic activity. Compound 8e binds to HSA readily with a binding constant of 1.32 × 10⁵ M^-1, indicating that the compound could be delivered to the target site effectively. Compound 8e can also form a supramolecular complex with DNA to obstruct DNA replications. These results suggest that analogue 8e could be further developed as a potential Antibacterial agent. Furthermore, the cytotoxicity of all the synthesized compounds was evaluated against 60 human Cancer cell lines to test their potential for Anticancer agents.

Antibacterial activity; Drug resistance; HSA and DNA interactions; Membrane disruption; Metabolic activity; Naphthalimide-triazine.