Heteroaryl Bishydrazono Nitroimidazoles: A Unique Structural Skeleton with Potent Multitargeting Antibacterial
Zhen-Zhen Li1,2, Cheng-He Zhou2, Yi-Jin Liu1
1State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Frontiers Science Center for Cell Responses, College of Pharmacy, Nankai University, Tianjin 300071, China.
Abstract:
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 4 displayed a broad-spectrum antibacterial profile with low cytotoxicity and hemolysis. It could inhibit the proliferation of methicillin-resistant Staphylococcus aureus and reduce its metabolic activity with low bacterial resistance. Further investigations revealed that the highly active compound 4 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 4-DNA gyrase complex and cause cell death. These results demonstrated that compound 4 should have large potential as a promising candidate in the ongoing battle against resistant bacterial infections.
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