Heteroarylcyanovinyl Benzimidazoles as New Antibacterial Skeleton with Large Potential To Combat Bacterial Infections

This work developed a class of unique heteroarylcyanovinyl benzimidazoles (HBs) as a new structural skeleton of potential multitargeting antibacterial agents to confront dreadful <i>Staphylococcus aureus</i> infections in the livestock industry. Some target compounds exhibited effective antibacterial activities against the tested strains. Especially, HB <b>36c</b> with a 5-fluorobenzimidazole ring exerted excellent inhibitory activity toward <i>Staphylococcus aureus</i> ATCC 29213 with a low MIC value of 0.001 mM, being 13-fold more active than norfloxacin. Compound <b>36c</b> displayed inconspicuous hemolytic rate, low cytotoxicity, and good pharmacokinetics. Moreover, compound <b>36c</b> could effectively eliminate bacterial biofilms and block the development of resistance, implying its large potential as a drug candidate. Preliminary mechanistic investigations revealed that compound <b>36c</b> could destroy the bacterial membrane, trigger bacterial oxidative stress, intercalate into DNA, and bind with DNA gyrase B, which showed multitargeting antibacterial potential. These findings suggested that heteroarylcyanovinyl benzimidazoles might provide new promise as potential new structural multitargeting antibacterial agents for the prevention and treatment of <i>Staphylococcus aureus</i> in the livestock industry.