Levofloxacin is a widely used fluoroquinolone in several infectious diseases. The structure–activity relationship of levofloxacin has been studied. However, the effect of changing the carbonyl into thiocarbonyl of levofloxacin has not been investigated up to the date of this report. In this work, levofloxacin structure was slightly modified by making a thionated form (compound 3), which was investigated for its antibacterial activity, biocompatibility, and cytotoxicity, as well as spectroscopic properties. The antibacterial susceptibility testing against five different bacteria showed promising minimum inhibitory concentrations (MICs), particularly against B. spizizenii and E. coli, with an MIC value of 1.9 µM against both bacteria, and 7.8 µM against P. mirabilis. The molecular docking experiment showed similar binding interactions of both levofloxacin and compound 3 with the active site residues of topoisomerase IV. The biocompatibility and cytotoxicity results revealed that compound 3 was more biocompatible with normal cells and more cytotoxic against cancer cells, compared to levofloxacin. Interestingly, compound 3 also showed an excitation profile with a distinctive absorption peak at λ_max 404 nm. Overall, our results suggest that the thionation of quinolones may provide a successful approach toward a new generation with enhanced pharmacokinetic and safety profiles and overall activity as potential antibacterial agents.

Background: From a chemistry point of view, we hypothesized that superlative dual cytotoxicity-radical scavenging bioefficacies of series 4 FQs correlate to their acidic groups and C8-C7 ethylene diamine Chelation Bridge. Methodology: Newly synthesized 16 lipophilic-acid chelating FQs have been screened for in vitro duality of proliferation inhibition and radical scavenging capacities. Results: Substantially in LPS prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of new FQs’ NO scavenging/antiinflammation capacity were 4e<4b<3d<4f<5c0.05). In comparison to classical and robust antineoplastic agent cisplatin and unlike triazoloFQs; nitroFQs (3a, 3b and 3f) and the reduced FQs (4a, 4c, 4d and 4e) exerted antiproliferation IC50 values <50 µM in leukaemia K562. Besides nitroFQ 3, the reduced FQs (4c and 4f) exhibited antineoplastic IC50 values <50 µM in lung A549 carcinoma. NitroFQ 3c and reduced FQs 4b, 4c, and 4f in breast MCF7 and reduced 4c in pancreatic PANC1 had reduction of viability IC50 values <50 µM. NitroFQ 3e, reduced FQs 4b and, 4c and triazoloFQ 5a exerted antiproliferation IC50 values <50 µM in breast T47D cells. Also nitroFQ 3e, reduced FQ 4c and triazoloFQ 5f exhibited antineoplastic IC50 values <50 µM in PC3 prostate cancer cells. Exceptionally triazoloFQ 5a, but neither nitro- nor reduced FQs, had cytotoxicity IC50 value <50 µM in resistant melanoma A375 cells. Unequivocally 4b antineoplastic effectiveness linked with its radical scavenging and antiinflammation effects while 3d and 5c lacked matching antiproliferation potentialities to their exquisite antiinflammation capacities. Explicitly reduced 4e and 4f exerted antiinflammation-selective cytotoxicity duality in vitro. Conclusion: Collectively, this work reveals lipophilic-acidic chelator FQs as authentic agents for the repurposing approach in anticancer chemotherapy/prevention.