Novel aminothiazoximone-corbelled ethoxycarbonylpyrimidones with antibiofilm activity to conquer Gram-negative bacteria through potential multitargeting effects

Abstract

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.0066 mmol/L than norfloxacin. It was also revealed that imidazolyl ACE 6c not only possessed inconspicuous hemolytic rate and cytotoxicity, low drug resistance and no risk of penetrating the blood-brain barrier, but also exhibited obvious biofilm inhibition and eradication activities. The preliminary mechanism research suggested that imidazolyl ACE 6c could induce metabolic dysfunction by deactivating lactate dehydrogenase and promote the accumulation of reactive oxygen species to decrease the reduced glutathione and ultimately cause oxidative damage in bacteria. Furthermore, ACE 6c was also found that could insert into DNA to form the supramolecular complex of 6c-DNA and trigger cell death. The multidimensional effect might promote bacterial cell rupture, leading to the leakage of intracellular content. These findings manifested that novel imidazolyl ACE 6c as a potential multitargeting antibacterial agent with potent antibiofilm activity could provide new possibility for the treatment of refractory biofilm-intensified bacterial infections.