Hydrazyl hydroxycoumarins as new potential conquerors towards Pseudomonas aeruginosa

A class of unique hydrazyl hydroxycoumarins (HHs) as novel structural scaffold was developed to combat dreadful Bacterial infections. Some HHs could effectively suppress Bacterial growth at low concentrations, especially, pyridyl HH 7 exhibited a good inhibition against Pseudomonas aeruginosa 27853 with a low MIC value of 0.5 μg/mL, which was 8-fold more active than norfloxacin. Furthermore, pyridyl HH 7 with low hemolytic activity and low cytotoxicity towards NCM460 cells showed much lower trend to induce the drug-resistant development than norfloxacin. Preliminarily mechanism exploration indicated that pyridyl HH 7 could eradicate the integrity of Bacterial membrane, result in the leakage of intracellular proteins, and interact with Bacterial DNA gyrase via non-covalent binding, and ADME analysis manifested that compound 7 gave good pharmacokinetic properties. These results suggested that the newly developed hydrazyl hydroxycoumarins as potential multitargeting Antibacterial agents should be worthy of further investigation for combating Bacterial infection.

Antibacterial; Coumarin; Hydrazyl; Membrane; Pseudomonas aeruginosa.