Novel hybrids of metronidazole and quinolones: Synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin

• Synthesis of a novel series of hybrids of metronidazole and quinolones.
• Valuable antimicrobial potency and broad spectrum for some prepared hybrids.
• No toxicity of metronidazole–quinolones hybrids to A549 and hepatocyte cells.
• Competitive interactions of strong active compound with metal ions to HSA.
• Experimental results showing stronger binding ability with topo IV than norfloxacin.

A novel series of hybrids of metronidazole and quinolones as antimicrobial agents were designed and synthesized. Most prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. Furthermore, these highly active metronidazole–quinolone hybrids showed appropriate ranges of pKa, log P and aqueous solubility to pharmacokinetic behaviors and no obvious toxicity to A549 and human hepatocyte LO2 cells. Their competitive interactions with metal ions to HSA revealed that the participation of Mg2+ ion in compound 7d–HSA association could result in a concentration increase of free compound 7d. Molecular modeling and experimental investigation of compound 7d with DNA suggested that possible antibacterial mechanism might be in relation with multiple binding sites between bioactive molecules and topo IV–DNA complex.

A series of metronidazole–quinolones hybrids were designed and synthesized. Their antimicrobial activities, pKa, cytotoxicity, preliminary antimicrobial mechanism and their transportation by HSA were studied.Figure optionsDownload as PowerPoint slide