Heteroaryl Bishydrazono Nitroimidazoles: A Unique Structural Skeleton with Potent Multitargeting Antibacterial Activity

The emergence of bacterial infections as a critical public health challenge underscores the urgent need for innovative therapeutic strategies. We designed and synthesized a series of novel heteroaryl bishydrozono nitroimidazoles and their analogs by strategically hybridizing multiple molecular components through diverse linkers. Among the newly synthesized compounds, compound <b>4</b> displayed a broad-spectrum antibacterial profile with low cytotoxicity and hemolysis. It could inhibit the proliferation of methicillin-resistant <i>Staphylococcus aureus</i> and reduce its metabolic activity with low bacterial resistance. Further investigations revealed that the highly active compound <b>4</b> could not only disrupt cell membrane integrity and induce excessive reactive oxygen species within bacterial membranes, but also intercalate into DNA to form a supramolecular <b>4</b>-DNA gyrase complex and cause cell death. These results demonstrated that compound <b>4</b> should have large potential as a promising candidate in the ongoing battle against resistant bacterial infections.