Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents

• DOI: 10.1016/j.ejmech.2019.06.071
• Publication Date: 2019-06-27T16:13:58Z
• Authors: Joanna Fedorowicz; Jarosław Sączewski; Agnieszka Konopacka; Krzysztof Waleron; Dawid Lejnowski; Krzesimir Ciura; Tihomir Tomašič; Žiga Skok; Kirsi Savijoki; Małgorzata Morawska; Shella Gilbert-Gi...; Adyary Fallarero
• Keywords: DNA Topoisomerase IV; Quinolone; FLUOROQUINOLONES; STREPTOCOCCUS-PNEUMONIAE; Pharmacy; Microbial Sensitivity Tests; CIPROFLOXACIN; Quinolones; Gram-Positive Bacteria; Drug synthesis; Structure-Activity Relationship; 03 medical and health sciences; Gram-Negative Bacteria; DRUG ACCUMULATION; Humans; PERMEABILITY; MICELLAR ELECTROKINETIC CHROMATOGRAPHY; Enzyme Inhibitors; STAPHYLOCOCCUS-AUREUS; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; DERIVATIVES; Hybrid compounds; RAPID COLORIMETRIC ASSAY; EFFLUX PUMPS; Anti-Bacterial Agents; 3. Good health; Quaternary Ammonium Compounds; Enzyme inhibition; HEK293 Cells; Chemical sciences; DNA Gyrase; Molecular docking; Antibacterial activity

A series of novel fluoroquinolone-Safirinium dye hybrids was synthesized by means of tandem Mannich-electrophilic amination reactions from profluorophoric isoxazolones and antibiotics bearing a secondary amino group at position 7 of the quinoline ring. The obtained fluorescent spiro fused conjugates incorporating quaternary nitrogen atoms were characterized by 1H NMR, IR, MS, and elemental analysis. All the synthetic analogues (3a-h and 4a-h) were evaluated for their in vitro antimicrobial, bactericidal, and antibiofilm activities against a panel of Gram positive and Gram-negative pathogenic bacteria. The most active Safirinium Q derivatives of lomefloxacin (4d) and ciprofloxacin (4e) exhibited molar-based antibacterial activities comparable to the unmodified drugs and displayed considerable inhibitory potencies in E. coli DNA gyrase supercoiling assays with IC50 values in the low micromolar range. Zwiterionic hybrids were noticeably less lipophilic than the parent quinolones in micellar electrokinetic chromatography (MECK) experiments. The tests performed in the presence of phenylalanine-arginine β-naphthylamide (PAβN) or carbonyl cyanide m-chlorophenylhydrazone (CCCP) revealed that the conjugates are to some extent subject to bacterial efflux and cellular accumulation, respectively. Moreover, the hybrids did not exhibit notable cytotoxicity towards the HEK 293 control cell line and demonstrated low propensity for resistance development, as exemplified for compounds 3g and 4b. Finally, molecular docking experiments revealed that the synthesized compounds were able to bind in the fluoroquinolone-binding mode at S. aureus DNA gyrase and S. pneumoniae topoisomerase IV active sites.