Discovery of Benzimidazole Quinolone Hybrids as New Cleaving Agents towards Drug-resistant P. aeruginosa DNA.

Authors：Zhou Cheng He; Wang Ya Nan; Bheemanaboina Rammohan R Yadav; Gao Wei Wei; Kang Jie; Cai Gui Xin

Source：ChemMedChem, 2018.

DOI：10.1002/cmdc.201700739

• Quinolone * Benzimidazole * Antibacterial * Antifungal * DNA

A series of benzimidazole quinolone hybrids as new potential antimicrobial agents were designed and synthesized, and their bioactive assay indicated that some prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5b showed remarkable antimicrobial activities against the resistant P. aeruginosa and C. tropicalis isolated from infected patients. The active molecule 5b could not only rapidly kill the tested strains, but also exhibit low toxicity towards Hep-2 cells. It was more difficult than norfloxacin to trigger the development of bacterial resistance against P. aeruginosa. Molecular docking demonstrated that it could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5b. Preliminary experimental mechanism exploration suggested that derivative 5b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but it was able to cleave DNA effectively, which might further block DNA replication to exert the powerful bioactivities. In addition, compound 5b was found to be a promising antibacterial agent with membrane disruption ability.

• Institution
  2