Synthesis and antibacterial activity evaluation of N (7) position-modified balofloxacins.

A series of small-molecule fluoroquinolones were synthesized, characterized by HRMS and NMR spectroscopy, and screened for their antibacterial activity against MRSA, P. aeruginosa, and E. coli as model G+/G- pathogens. Compounds 2-e, 3-e, and 4-e were more potent than the reference drug balofloxacin against MRSA and P. aeruginosa (MIC values of 0.0195 and 0.039 µg/ml for 2-e, 0.039 and 0.078 µg/ml for each of 3-e and 4-e, respectively). Analysis of the time-dependent antibacterial effect of compound 2-e toward MRSA showed that in the early logarithmic growth phase, bactericidal effects occurred, while in the late logarithmic growth phase, bacterial inhibition occurred because of concentration effects and possibly the development of drug resistance. Compound 2-e exhibited low toxicity toward normal mammalian cell lines 3T3 and L-02 and tumor cell lines A549, H520, BEL-7402, and MCF-7. The compound was not hemolytic. Atomic force microscopy (AFM) revealed that compound 2-e could effectively destroy the membrane and wall of MRSA cells, resulting in the outflow of the cellular contents. Docking studies indicated the good binding profile of these compounds toward DNA gyrase and topoisomerase IV. ADMET's prediction showed that most of the synthesized compounds followed Lipinski's "rule of five" and possessed good drug-like properties. Our data suggested that compound 2-e exhibited potent anti-MRSA activity and is worthy of further investigation.

Biochar of Spent Coffee Grounds as Per Se and Impregnated with TiO2: Promising Waste-Derived Adsorbents for Balofloxacin.

Biochars (BC) of spent coffee grounds, both pristine (SCBC) and impregnated with titanium oxide (TiO2@SCBC) were exploited as environmentally friendly and economical sorbents for the fluroquinolone antibiotic balofloxacin (BALX). Surface morphology, functional moieties, and thermal stabilities of both adsorbents were scrutinized using SEM, EDS, TEM, BET, FTIR, Raman, and TG/dT analyses. BET analysis indicated that the impregnation with TiO2 has increased the surface area (50.54 m2/g) and decreased the pore size and volume. Batch adsorption experiments were completed in lights of the experimental set-up of Plackett-Burman design (PBD). Two responses were maximized; the % removal (%R) and the adsorption capacity (qe, mg/g) as a function of four variables: pH, adsorbent dosage (AD), BALX concentration ([BALX]), and contact time (CT). %R of 68.34% and 91.78% were accomplished using the pristine and TiO2@SCBC, respectively. Equilibrium isotherms indicated that Freundlich model was of a perfect fit for adsorption of BALX onto both adsorbents. Maximum adsorption capacity (qmax) of 142.55 mg/g for SCBC and 196.73 mg/g for the TiO2@SCBC. Kinetics of the adsorption process were best demonstrated using the pseudo-second order (PSO) model. The adsorption-desorption studies showed that both adsorbents could be restored with the adsorption efficiency being conserved up to 66.32% after the fifth cycles.

Development and Validation of Stability-Indicating HPLC Methods for the Estimation of Lomefloxacin and Balofloxacin Oxidation Process under ACVA, H2O2, or KMnO4 Treatment. Kinetic Evaluation and Identification of Degradation Products by Mass Spectrometry.

The oxidation of lomefloxacin (LOM) and balofloxacin (BAL) under the influence of azo initiator of radical reactions of 4,4'-azobis(4-cyanopentanoic acid) (ACVA) and H2O2 was examined. Oxidation using H2O2 was performed at room temperature while using ACVA at temperatures: 40, 50, 60 °C. Additionally, the oxidation process of BAL under the influence of KMnO4 in an acidic medium was investigated. New stability-indicating HPLC methods were developed in order to evaluate the oxidation process. Chromatographic analysis was carried out using the Kinetex 5u XB-C18 100A column, Phenomenex (Torrance, CA, USA) (250 × 4.6 mm, 5 µm particle size, core shell type). The chromatographic separation was achieved while using isocratic elution and a mobile phase with the composition of 0.05 M phosphate buffer (pH = 3.20 adjusted with o-phosphoric acid) and acetonitrile (87:13 v/v for LOM; 80:20 v/v for BAL). The column was maintained at 30 °C. The methods were validated according to the ICH guidelines, and it was found that they met the acceptance criteria. An oxidation process followed kinetics of the second order reaction. The most probable structures of LOM and BAL degradation products formed were assigned by the UHPLC/MS/MS method.

Sericin-functionalized GNPs potentiate the synergistic effect of levofloxacin and balofloxacin against MDR bacteria.

A gradual expansion in resistant bacterial strains against commercially available antibacterial agents is the serious concern of the given research. It poses critical problem for public health. Thus, the demand for new antimicrobial agents has increased the interest in newer technologies and innovative approaches are required to advance the diagnosis and elimination of causative organisms. In this study, the potential role of technologies based on gold nanoparticles (GNPs) has been evaluated. GNPs were synthesized by using a cysteine protease, sericin whose reducing properties were exploited to bioengineer NPs (SrGNPs) where sericin with the help of thiol groups encapsulated over the surface of GNPs. Further, SrGNPs were bioconjugated with levofloxacin (Levo) and balofloxacin (Balo) to increase the efficacy of these drugs. Here, the antibacterial action of SrGNPs and their bioconjugated counterparts comprising Levo (Levo-SrGNPs), Balo (Balo-SrGNPs), and Levo/Balo (Levo-Balo-SrGNPs) were examined against normal and multi-drug resistant (MDR) strains of E. coli and S. aureus. The minimum inhibitory concentration (MIC) of these bioconjugates against said bacteria were found less than their pure counterparts. Further, the synergistic role of SrGNPs in combination with Levo and Balo was also explained using Chou-Talalay (C-T) method. The synthesis and bioconjugation of SrGNPs were confirmed by UV-visible spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and zeta-potential.

Preparation, Characterization, and Properties of Inclusion Complexes of Balofloxacin with Cyclodextrins.

The study mainly aimed to improve the aqueous solubility of Balofloxacin (BLFX) by preparing the inclusion complexes (ICs) of BLFX with cyclodextrins (CDs). In this study, ICs in solid state were obtained by using beta-CD (ß-CD), 2-hydroxypropyl-ß-CD (HP-ß-CD), 2, 6-dimethyl-ß-CD (DM-ß-CD) through a freeze-drying technique. The formation of ICs was confirmed through Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, nuclear magnetic resonance, and scanning electron microscopy. Results demonstrated that the water solubility and dissolution rates of three ICs were distinctly improved than that of parent BLFX. Bacteriostatic experiment manifested that the antibacterial effect of BLFX was not inhibited after encapsulation in CDs. The damage of BLFX to kidney and liver cells was reduced. Consequently, successful preparation of the ICs of BLFX with CDs provided possibility for devising new dosage form of BLFX, which held great promise for further applications in clinical fields.

Characterization of balofloxacin-stressed proteomics and identification of balofloxacin-binding proteins pre-peptidase and integration host factor in Edwardsiella tarda.

The overuse of antibiotics to control bacterial pathogens leads to the generation of their antibiotic-resistant strains including Edwardsiella tarda. Understanding of mechanisms of the antibiotic resistance is crucial to develop novel methods to manage the infection. Here, two-dimensional electrophoresis-based proteomics was used to characterize balofloxacin-responsive proteins. The altered proteome consisted of 19 proteins with differential abundance, where six metabolic pathways were enriched. The metabolic modulation activated the central carbon metabolism with elevation of NADH, PMF, and ATP. Among the 19 proteins, ETAE_1987 (pre-peptidase) and ETAE_2174 (integration host factor beta subunit) were bound with balofloxacin directly. This was further confirmed by the binding of balofloxacin with recombinant ETAE_1987 and ETAE_2174 using Oxford cup method. Compared with bovine serum albumin, a known balofloxacin-binding protein, ETAE_1987 and ETAE_2174 increased the binding capability by 3.3- and 22-fold, respectively. The combination was validated by microscale thermophoresis. These data characterize the balofloxacin-stressed proteome as a result of the increased central carbon metabolism and energy metabolism and determine ETAE_1987 and ETAE_2174 as balofloxacin-binding proteins. These findings have significant implications in understanding bacterial antibiotic-resistant and drug action mechanisms based on balofloxacin-binding proteins. SIGNIFICANCE: Antibiotic-resistant Edwardsiella tarda strains are frequently isolated and cause a great loss in aquaculture since these bacterial strains are insensitivity to antibiotics. The present study showed that the increased central carbon metabolism forms a characteristic feature of the balofloxacin-stressed proteomics. Furthermore, two proteins, ETAE_1987 (pre-peptidase) and ETAE_2174, of the balofloxacin-stressed proteome were identified as balofloxacin-binding proteins. The binding capability is 0.39 ±â€¯0.017 and 2.67 ±â€¯0.066 ng/µg proteins for ETAE_1987 and ETAE_2174, respectively. These results reveal the elevated central carbon metabolism as a key feature of the balofloxacin-stressed proteomics and pre-peptidase and integration host factor as balofloxacin-binding proteins in E. tarda. These findings are useful in the understanding of bacterial balofloxacin-stressed mechanisms and providing new targets for controlling antibiotic-resistant bacteria.

Farmacocinética plasmática de la balofloxacina en terneros / Farmacocinética plasmática de balofloxacin em bezerros / Plasma pharmacokinetic of balofloxacin in calves

Los parámetros farmacocinéticos de absorción y disposición de balofloxacina se determinaron en terneros hembras raza holando-argentino (n = 6), luego de una dosis única de 5 mg/kg administrada en bolo intravenoso y subcutáneo, en un diseño cruzado de tratamiento. El analito se determinó en muestras de plasma por método microbiológico de difusión en agar utilizando como microorganismo detector una solución de esporas de Bacillus subtilis BGA y medio de cultivo Antibiotic Nº 1. Las concentraciones plasmáticas de balofloxacina en función del tiempo se analizaron por el modelo cinético no compartimental utilizando el software PK Solution 2.0. Los parámetros farmacocinéticos obtenidos fueron para la vía intravenosa: t1/2  = 2.3 ± 1.1 h; Cltotal área= 10.2 ± 3.4 ml/min/kg; Vdárea= 1.8 ± 0.3 L/kg; ABCárea= 551.3 ± 247.0 g/min/ml. Excepto para CltotaL área y ABCárea, los valores obtenidos para la administración intravenosa difirieron significativamente de los obtenidos del ensayo por vía subcutánea (p<0.05), para el cual se obtuvo un Cmáx= 1.3 ± 0.4 g/ml, con un tmáx= 51 ± 12.1 minutos y una biodisponibilidad cercana al 98%. El valor de Vdárea superior a 1 l/kg obtenido con ambas vías de aplicación indica buena capacidad para difundir a territorios extravasculares y tejidos.

Pharmacokinetic parameters of absorption and disposition of balofloxacin were determined in female Holando-Argentinean calves (n = 6), after a 5 mg/kg single dose, administered as both intravenous and subcutaneous bolus, in a crossed-over design treatment. The analyte was determined in plasma samples by microbiological method in agar diffusion, using a Bacillus subtilis BGA spore solution as microorganism detector in agar Antibiotic Nº 1. The plasmatic concentrations of balofloxacin based on the time were analyzed by a non compartimental kinetic model using software PK Solution 2.0. The intravenous pharmacokinetic parameters obtained were: t1/2β= 2.3 ± 1.1 h; Cltotal area= 10.2 ± 3.4 ml/min/kg; Vdárea= 1.8 ± 0.3 L/kg; and AUCárea= 551.3 ± 247.0 μg/min/ml. Except for Cltotal area and AUCarea, the values obtained for the intravenous administration significantly differed from the obtained ones for the subcutaneous route (p<0.05), for which Cmax= 1.3 ± 0.4 μg/ml, tmax= 51 ± 12.1 minutes and bioavailability values close to 98% were obtained. The Vdarea value was superior to 1 l/kg for both routes of application and indicates good capacity to spread to extravascular area and tissues.

Os parâmetros farmacocinéticos de absorção e eliminação dos balofloxacin foi determinada nos bezerros Holando-argentina (n = 6), depois de uma dose única de 5 mg/kg, uma vez que ambos foram administrados em bolus por via intravenosa e subcutânea, em um design de tratamento cruzado. O analito foi determinado em amostras de plasma por método microbiológico de difusão em ágar, utilizando uma solução de esporos de microorganismo Bacillus subtilis BGA como detector em ágar antibiótica Nº 1. As concentrações plasmáticas de balofloxacin com base no tempo não foram analisados por um modelo de cinética compartimental usando software PK Solução 2,0. O parâmetros farmacocinéticos da via intravenosa obtidos foram: t1/2 β = 2.3 ± 1.1 h; Cltotal área = 10.2 ± 3.4 ml / min / kg; Vdárea = 1.8 ± 0.3 l/kg; e AUCárea = 551,3 ± 247,0 μg/min/ml. Exceto para Cltotal área e AUCárea, os valores obtidos para a administração intravenosa diferiu significativamente do obtido para a via subcutânea, (p<0,05), para a qual Cmax = 1.3 ± 0.4 μ g/ml, tmax = 51 ± 12.1 minutos e biodisponibilidade perto de 98% foram obtidos. O valor Vdarea foi superior a 1 l/kg para ambas as vias de aplicação e indica uma boa capacidade de propagação de espaço extravascular e tecidos.

Balofloxacin and levofloxacin in the treatment of 215 cases of bacterial infections in urinary system lower respiratory tract / 重庆医科大学学报

0.05).Conclusion:Balofloxacin is as effective and well-tolerated as levofloxacin for the treatment of bacterial infections in urinary system respiratory tract.

A Multi-center Study to Evaluate the Efficacy and Safety of Balofloxacin and Ofloxacin for Patients with Uncomplicated Urinary Tract Infection / 대한비뇨기과학회지

PURPOSE: Balofloxacin is a new fluoroquinolone antibiotic that has potent, broad-spectrum, antimicrobial activity and a good safety profile during preclinical study. The aim of this study was to evaluate the efficacy and safety of balofloxacin in comparison with those of ofloxacin for uncomplicated urinary tract infections. MATERIALS AND METHODS: Patients randomly received oral balofloxacin at 100mg twice a day or oral ofloxacin at 200mg twice a day for 5 days at a ratio of 2:1. Efficacy was assessed by the eradication rate of baseline pathogens and clinical outcome of the objective disease. Safety was assessed by adverse events, changes in laboratory tests and vital signs. RESULTS: The bacteriological efficacy rate was 83.9%(99/118) in the balofloxacin group and 88.4%(61/69) in the ofloxacin group. In the equivalence test using 15% as the standard, clinically acceptable difference value of efficacy, balofloxacin was equivalent to ofloxacin [95% CI: -14.6% to 5.5%]. The bacteriological evaluation of the case whose baseline pathogen was susceptible to the study drug was 96.6%(84/87) for the balofloxacin group and 92.6%(50/54) for the ofloxacin group [95% CI: -4.0% to 11.9%], thereby demonstrating equivalence; as did the relatively high clinical success rates of 99.2% and 95.7%, respectively. The adverse event rate and the drug-related adverse event rate for the balofloxacin group was significantly lower than that of the ofloxacin group(p=0.036, 0.031). Neither unusual laboratory findings nor abnormal vital signs were reported for either group and there were no significant differences between the treatment groups. CONCLUSIONS: Twice daily administration of 100mg balofloxacin is as effective as twice daily administration of 200mg ofloxacin for the treatment of uncomplicated urinary tract infections. With regard to safety, balofloxacin was confirmed to be safer than ofloxacin.

Pharmacokinetics of Balofloxacin Tablets in Chinese Healthy Volunteers / 中国药房

OBJECTIVE:To study the pharmacokinetics of balofloxacin tablets in Chinese healthy volunteers.METHODS:A single dose of 100 or 200 mg balofloxacin tablets were given to 12 healthy volunteers in a randomized crossover design.Concentrations of balofloxacin in plasma and urine were determined by HPLC with data processed by DAS(drug and statistics)software.RESULTS:After administration of balofloxacin 100 mg and 200 mg,the Cmax were(0.970?0.245)?g?mL-1 and(1.849?0.466)?g?mL-1;the tmax were(1.25?1.10)h and(1.24?0.81)h;the t1/2 were(7.14?1.01)h and(7.11?0.72)h;the AUC0～36 were(7.309?1.368)?g?h?mL-1 and(15.214?1.727)?g?h?mL-1;AUC0～∞ were(7.531?1.386)?g?h?mL-1 and(15.695?1.762)?g?h?mL-1;the accumulative eliminating rates within 36 h in urine were(64.47?11.56)% and(63.24?11.93)%,respectively.CONCLUSION:The pharmacokinetics of balofloxacin in healthy volunteer after oral administration was characterized by high peak concentration and long half life.The method is sensitive,accurate,reliable and specific,and can satisfy the requirements for pharmaceutical study.