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Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin (1), and its analogs (2-24) were tested against bloodstream forms of T. brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, T. equiperdum, and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX (1)] demonstrated selective trypanocidal activity against T. congolense (IC 50 7.79 µM; SI 39.6), whereas the CPX derivatives (2-10) showed weak selective activity (25 < IC 50  < 65 µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids (11-24) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX (1); CPX amide derivatives 18: IC 50 8.95 µM; SI 16.84; 22: IC 50 5.42 µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC 50 4.51 µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho-, meta-, and/or para-substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.

Sarafloxacin (SAR), one of the most widely used fluoroquinolone antibiotics, is a serious threat to aquatic environments and human health due to its illegal abuse. Herein, we first screened an aptamer (SAR-1) that specifically binds to SAR using capture-SELEX technology. Based on molecular docking technology, SAR-1 was gradually truncated, and a short SAR-1a with better affinity and specificity was obtained. The optimal SAR-1a was further combined with a Pt nanoparticle (Pt NP)- decorated bimetallic Fe/Co-MOF to fabricate a multimode sensing platform for SAR determination. The Fe/Co-MOF@Pt NPs exhibited excellent peroxidase-like activity, which catalyzed the H 2 O 2 -mediated oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), thereby enabling visual detection of SAR. Meanwhile, the generated oxTMB can also produce SERS responses and be used for the SERS detection of SAR. Moreover, the inherent fluorescence property of Fe/Co-MOF@Pt NPs enabled fluorescence detection of SAR. The designed triple-readout aptasensor showed good sensitivity for SAR detection with limits of detection of 0.125 ng/mL (fluorescent mode) and 0.05 ng/mL (colorimetric and SERS mode). The aptamer-based triple-mode sensing platform provided mutual verification of detection results in different output modes, effectively improving the assay accuracy and providing a promising tool for highly sensitive, selective, and accurate determination of SAR in daily life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Avian salmonellosis is a group of diseases caused by bacteria from the genus Salmonella with a negative impact on poultry, particularly chickens. In addition, salmonellosis is a global food-borne infection., Aim: The aim of this study was to evaluate the effect of nano-emulsion difloxacin (NED) and commercial difloxacin (CD) water supplement on broiler's growth, feed intake, and body weight, weight gain, growth rate, feed conversion ratio (FCR), and mortality rate (MR). The antibiotic sensitivity was determined both in-vivo and in-vitro for NED against Salmonella enterica Serovar enteritidis in chickens., Methods: 1500 one-day of age chicks were grouped into five groups as follows: group 1 (G1) control negative group, G2 control positive group (infected and not treated), G3 (infected and treated with CD, and G4 and G5 (infected and treated with NED at different doses). Samples, including the intestine, liver, and spleen were collected. Agar well diffusion test and minimum inhibitory concentrations were adopted. Histopathological lesions on different tissues were studied. During 35 days of the experiment, the feed intake, growth rate, growth gain, FCR, and MR were recorded daily. In addition, a variety of analytical techniques including transmission electron microscopic analysis, dynamic light scattering, UV-visible spectroscopy, and zeta-potential analysis were applied to characterize NED., Results: The agar well diffusion test indicated that NED was in-vitro effective against S. enteritidis isolates than CD. The minimum inhibitory concentration was recorded as NED inhibited bacterial growth till well 8 at a concentration of 0.78 µg/ml; on the other hand, the CD inhibited bacterial growth till well 6 at a concentration of 0.62 µg/ml. Growth performance and MRs in the groups treated with NED are significantly reduced., Conclusion: Treatment of broiler's drinking water with NED at doses of 0.5 and 1 ml instead of pure CD was able to enforce a new perspective, antibacterial efficacy, enhancing the productive performance, and reducing the MRs of broilers., Competing Interests: The authors declare that there is no conflict of interest.

A flow-limited physiologically based pharmacokinetic (PBPK) model consisting of seven compartments was established for orbifloxacin in crucian carp to predict drug concentrations after intravenous or intramuscular injections. Physiological and anatomical parameters, including tissue weights and blood flow through different tissues, were obtained from previous literature. The tissue/plasma partition coefficients for orbifloxacin were calculated using the area method or parameter optimization. In addition, their values were 0.9326, 1.1204, 1.1644, 1.3514, and 2.0057 in the liver, skin, muscle, kidney, and the rest of the body compartment, respectively. Based on the current PBPK model, orbifloxacin concentrations were predicted and compared with those previously reported for further validation. In addition, the mean absolute percentage error (MAPE) values were also calculated, with values ranging from 10.21% in plasma to 42.37% in kidneys, indicating acceptable predictions for all tissues and plasma. A local sensitivity analysis was performed, which showed that the parameters related to elimination and distribution were most influential on orbifloxacin concentrations in muscle. This model was finally used to predict plasma and tissue concentrations after multiple intramuscular dosing. The current PBPK model provided a valuable tool for predicting the tissue residues of orbifloxacin in crucian carp following intramuscular injection., (© 2022 John Wiley & Sons Ltd.)

This study analyzed the pharmacokinetics of orbifloxacin (OBFX) in plasma, and its migration and retention in epithelial lining fluid (ELF) and alveolar cells within the bronchoalveolar lavage fluid (BALF). Four healthy calves received a single dose of OBFX (5.0 mg/kg) intramuscularly. Post-administration OBFX dynamics were in accordance with a non-compartment model, including the absorption phase. The maximum concentration (C max ) of plasma OBFX was 2.2 ± 0.1 μg/ml at 2.3 ± 0.5 hr post administration and gradually decreased to 0.3 ± 0.2 μg/ml at 24 hr following administration. The C max of ELF OBFX was 9.3 ± 0.4 μg/ml at 3.0 ± 2.0 hr post administration and gradually decreased to 1.2 ± 0.1 μg/ml at 24 hr following administration. The C max of alveolar cells OBFX was 9.3 ± 2.9 μg/ml at 4.0 hr post administration and gradually decreased to 1.1 ± 0.2 μg/ml at 24 hr following administration. The half-life of OBFX in plasma, ELF, and alveolar cells were 6.9 ± 2.2, 7.0 ± 0.6, and 7.8 ± 1.6 hr, respectively. The C max and the area under the concentration-time curve for 0-24 hr with OBFX were significantly higher in ELF and alveolar cells than in plasma (P<0.05). These results suggest that OBFX is distributed and retained at high concentrations in ELF and alveolar cells at 24 hr following administration. Hence, a single intramuscular dose of OBFX (5.0 mg/kg) may be an effective therapeutic agent against pneumonia.

Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multi-drug-resistant bacteria or 'superbugs'. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. The authors derivatized a clinically used fluoroquinolone antibiotic ciprofloxacin (Cip), and complexed it to a copper phenanthrene framework. This resulted in the development of two novel metallo-antibiotics of general formula [Cu(N,N)(CipHA)]NO 3 where N,N represents a phenanthrene ligand and CipHA represents a hydroxamic acid of Cip derivative. Comprehensive studies, including a detailed proteomic study in which Staphylococcus aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent antibacterial activity against S. aureus and methicillin-resistant S. aureus. In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to the innate immune system of mammals. These findings suggest that proteins involved in virulence, pathogenesis, and the synthesis of nucleotides and DNA repair mechanisms are most affected. In addition, both complexes affected similar cell pathways when compared with clinically used Cip, including cationic antimicrobial peptide resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2',3'-c]phenazine) analogue also induces cell leakage, which leads to an altered proteome indicative of reduced virulence and increased stress., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In addition to active pharmaceutical ingredient (API), antibiotics may contain small amounts of excipients and impurities and be prone to accumulation of degradation products. There has been limited work characterizing how these substances impact bacterial growth and antibiotic resistance development. We investigated how two ciprofloxacin (CIP) impurities, fluoroquinolonic acid (FQA) and ciprofloxacin ethylenediamine analogue (CEA), impact growth and antibiotic resistance in Escherichia coli. Additionally, we investigated how these impurities impact a frequently used API content assay. Both impurities displayed modest antimicrobial activity compared to the CIP API. The effective antimicrobial activity of a medicine containing increased impurity levels may permit bacterial growth and resistance development. Our results also suggest that increasing exposure concentration and duration to CEA and FQA, independent of CIP, can promote antibiotic resistance development. However, at concentrations of 100% and below the MIC of the API, impurities had limited contributions to resistance development compared to the CIP API. From a methodological standpoint, we found that UV spectrophotometry may be inadequate to account for antibiotic impurities or degradation products. This can lead to incorrect estimations of API content and we propose additional multi-wavelength measures when using UV spectrophotometry to help identify impurities or degradation., (© 2021 The Society for Applied Microbiology.)

Fluoroquinolones are targets of interest due to their broad spectrum antibacterial activity. Structure-activity relationship (SAR) of fluoroquinolones clearly indicates that substitution at C-7 position enhances the lipophilicity of these scaffolds resultantly affording pharmacologically significant compounds. Therefore, various ciprofloxacin-oxadiazole hybrids were synthesized and characterized by spectral analysis. Cytotoxic activity of these derivatives was assessed using human liver tumor cells (Huh7). One dose anticancer test results revealed moderate cytotoxicity of the newly synthesized compounds against this cell line. As the only compound 4a depicted comparatively lower cell viability value (81.91% using 100μg/mL concentration) than the other compounds.

We report herein design and synthesis of a new series of 3,7-bis-benzylidenes of ciprofloxacin. Most of the target compounds revealed good cytotoxic activity; the most potent 4e and 4i achieved strong broad spectrum antiproliferative activity with comparable activity to Doxorubicin with IC 50 ( µ M) of 1.21 ± 0.02, 0.87 ± 0.04, 1.21 ± 0.02; 0.41 ± 0.02, 0.57 ± 0.06, 1.31 ± 0.04 and 1.26 ± 0.01, 1.79 ± 0.04, 0.63 ± 0.01 against leukemia cancer cell line HL-60 (TB), colon cancer cell line HCT-116 and breast cancer cell line MCF7, respectively. Moreover, the most potent derivative 4i induced apoptosis at G2/M phase Investigating the mechanism of action of compounds 4e, 4 h and 4i exhibited promising dual TOP Iα and TOP IIB % inhibition comparable to Camptothecin and Etoposide; respectively. Docking of 4e, 4 h and 4i into the active site of topo I and II proteins compared to Camptothein and Etoposide revealed acceptable binding score and augmented enzyme assay data. Hence, 4e and 4i are promising targeted antiproliferative dual acting TOP Iα TOP IIB inhibitors that require further optimization., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Monodisperse restricted-access media bi-functional monomers with molecularly imprinted polymers (RAM-MIPs) were constructed using surface-initiated atom transfer radical polymerization. They were used as solid-phase extraction (SPE) adsorbents to enrich sarafloxacin (SAR) residues from egg samples, and influences on their performance were investigated. Optimum synthesis of RAM-MIPs was achieved by combining a bi-functional monomer (4-vinylpyridine-co-methacrylic acid, 1:3) with an 8:1:32:8 ratio of a template molecule, cross-linker, and restricted-access functional monomer. The SAR imprinting factor of RAM-MIPs was 6.05 and the selectivity coefficient between SAR and other fluoroquinolones was 1.86-2.64. Compared with traditional MIPs, the RAM-MIPs showed better SAR enrichment and selectivity during extraction of a complex protein-containing solution. Empty SPE cartridges were filled with RAM-MIP microspheres as SPE adsorbents. The limit of quantitation for SAR was 4.23 ng g -1 (signal-to-noise ratio = 10) and the mean SAR recovery from spiked egg samples was 94.0-101.3%. Intra-day and inter-day relative standard deviations were 1.1-9% and 1.5-3.3%, respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Drugs against flaviviruses such as dengue (DENV) and Zika (ZIKV) virus are urgently needed. We previously demonstrated that three fluoroquinolones, ciprofloxacin, enoxacin, and difloxacin, suppress replication of six flaviviruses. To investigate the barrier to resistance and mechanism(s) of action of these drugs, DENV-4 was passaged in triplicate in HEK-293 cells in the presence or absence of each drug. Resistance to ciprofloxacin was detected by the seventh passage and to difloxacin by the tenth, whereas resistance to enoxacin did not occur within ten passages. Two putative resistance-conferring mutations were detected in the envelope gene of ciprofloxacin and difloxacin-resistant DENV-4. In the absence of ciprofloxacin, ciprofloxacin-resistant viruses sustained a significantly higher viral titer than control viruses in HEK-293 and HuH-7 cells and resistant viruses were more stable than control viruses at 37 °C. These results suggest that the mechanism of action of ciprofloxacin and difloxacin involves interference with virus binding or entry., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC 50  = 2.53, 2.01, 17.36, 12.23 and 3.1 μM for HCT-116 cells, respectively and IC 50  = 0.73, 0.64, 3.32, 13.72 and 1.17 μM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIβ with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3, -8, and -9), release of cytochrome C from mitochondria, upregulation of proapoptotic Bax and down-regulation of Bcl-2 protein level. Thus, the new ciprofloxacin derivative 3j could be considered as a potential lead for further optimization of antitumor agent against leukemia and colorectal carcinoma., (Copyright © 2020. Published by Elsevier Inc.)

Background: Increasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context., Objective: In this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure-activity relationship) characterisation studies., Methods: A nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO 3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by 1 H, 13 C- NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli)., Results: The compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16 nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacin-derivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125 μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays., Conclusion: The results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.

The objective of this study was to investigate the effects of difloxacin (DIF) and avermectin (AVM) on glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T) in different tissues of crucian carp (Carassius auratus gibelio). After the treatments of DIF and AVM, the mRNA expressions of GAD and GABA-T in different tissues were detected by quantitative real-time PCR (qPCR). The results showed that the mRNA expressions of GAD 65 , GAD 67 , and GABA-T in the telencephalon (Tel), mesencephalon (Mes), cerebella (Cer), and medulla oblongata (Med) were downregulated significantly with the safe dose (SD, 20 mg/kg) of DIF (P < 0.05 or P < 0.01). While the expressions of GAD 65 and GAD 67 in the kidney at 12 h had strikingly upregulated to 13.81 ± 1.06** and 150.67 ± 12.85** times. Treated with the lethal dose of 50% (LD 50 , 2840 mg/kg b. W.) of DIF, the mRNA expressions of GAD 65 , GAD 67 , and GABA-T in all tissues were increased significantly (P < 0.01). The results of AVM group showed that the mRNA expressions of GAD 65 , GAD 67 , and GABA-T both in the central and peripheral tissues were all remarkably downregulated at the safe concentration (SC, 0.0039 mg/L) and the lethal concentration of 50% (LC 50 , 0.039 mg/L), except for the mRNA inhibitions of GAD 65 , GAD 67 , and GABA-T in the muscle at 2 h which sharply downregulated to 0.20 ± 0.02 ΔΔ  × 10 -2 , 0.57 ± 0.06 ΔΔ  × 10 -1 and 0.44 ± 0.02 ΔΔ  × 10 -1 , respectively (P < 0.01).

In the current study, eco-structured and efficient removal of the veterinary fluoroquinolone antibiotic sarafloxacin (SARA) from wastewater has been explored. The adsorptive power of four agro-wastes (AWs) derived from pistachio nutshells (PNS) and Aloe vera leaves (AV) as well as the multi-walled carbon nanotubes (MWCNTs) has been assessed. Adsorbent derived from raw pistachio nutshells (RPNS) was the most efficient among the four tested AWs (%removal '%R' = 82.39%), while MWCNTs showed the best adsorptive power amongst the five adsorbents (%R = 96.20%). Plackett-Burman design (PBD) was used to optimize the adsorption process. Two responses ('%R' and adsorption capacity ' q e ') were optimized as a function of four variables (pH, adsorbent dose 'AD' (dose of RPNS and MWCNTs), adsorbate concentration [SARA] and contact time 'CT'). The effect of pH was similar for both RPNS and MWCNTs. Morphological and textural characterization of the tested adsorbents was carried out using FT-IR spectroscopy, SEM and BET analyses. Conversion of waste-derived materials into carbonaceous material was investigated by Raman spectroscopy. Equilibrium studies showed that Freundlich isotherm is the most suitable isotherm to describe the adsorption of SARA onto RPNS. Kinetics' investigation shows that the adsorption of SARA onto RPNS follows a pseudo-second order (PSO) model.

A 20-year-old female mute swan ( Cygnus olor ) originally in a flock of free-living swans on a Long Island, New York, lake, was presented for facial swelling and decreased appetite. An adult male ring-billed gull ( Larus delawarensis ) was also presented to the same wildlife rescue center for bilateral lameness of 1-week duration. Once referred for veterinary evaluation and care, both species were diagnosed with septic arthritis and osteomyelitis caused by Chryseobacterium indologenes and treated with orbifloxacin until complete recovery. Chryseobacterium indologenes is infrequently diagnosed as an opportunistic pathogen in human medicine, and less so in veterinary medicine. In human patients, this bacterium is the cause of various infections, including meningitis, pneumonia, and implant failure. However, in veterinary medicine its pathogenicity has only been reported in fish, and sporadically mentioned as a culture result in tree frogs and turtles, where it was generally considered insignificant. In this report a clinical presentation, diagnosis, treatment, and outcome of osteomyelitis and septic arthritis caused by C indologenes is described in 1 anseriforme and in 1 charadriiforme species.

This paper describes the preparation, characterization, and evaluation of honey/tripolyphosphate (TPP)/chitosan (HTCs) nanofibers loaded with capsaicin derived from the natural extract of hot pepper ( Capsicum annuum L .) and loaded with gold nanoparticles (AuNPs) as biocompatible antimicrobial nanofibrous wound bandages in topical skin treatments. The capsaicin and AuNPs were packed within HTCs in HTCs-capsaicin, HTCs-AuNP, and HTCs-AuNPs/capsaicin nanofibrous mats. In vitro antibacterial testing against Pasteurella multocida, Klebsiella rhinoscleromatis, Staphylococcus pyogenes, and Vibrio vulnificus was conducted in comparison with difloxacin and chloramphenicol antibiotics. Cell viability and proliferation of the developed nanofibers were evaluated using an MTT assay. Finally, in vivo study of the wound-closure process was performed on New Zealand white rabbits. The results indicate that HTCs-capsaicin and HTCs-AuNPs are suitable in inhibiting bacterial growth compared with HTCs and HTCs-capsaicin/AuNP nanofibers and antibiotics ( P < 0.01). The MTT assay demonstrates that the nanofibrous mats increased cell proliferation compared with the untreated control ( P < 0.01). In vivo results show that the developed mats enhanced the wound-closure rate more effectively than the control samples. The novel nanofibrous wound dressings provide a relatively rapid and efficacious wound-healing ability, making the obtained nanofibers promising candidates for the development of improved bandage materials.

Here, we develop homogeneous hydrogel networks containing zinc tetraamino-phthalocyanine (ZnTAPc) as photosensitizer cross-linked with glutaraldehyde. The cross-linking process occurs via imine bond formation by reaction of NH 2 groups of ZnTAPc and chitosan with aldehyde groups of the glutaraldehyde. Insertion of ZnTAPc interestingly increases its solubility in water medium. 2.0% and 4% w/w of the ZnTAPc were used with respect to chitosan polymer to generate hydrogel photosensitizer. FT-IR and UV-Vis spectroscopy, scanning electron microscopy, and rheological measurements were applied to evaluate the properties of the prepared hydrogels. Finally, difloxacin HCl was selected as a fluoroquinolone drug for the assessment of the drug release features of the made hydrogels. The difloxacin release was affected by the amount of ZnTAPc and pH medium. The activity of the hydrogels in photosensitizing process was considered by computing the rate of 1,3-diphenylisobenzofuran adsorption reduction as a singlet oxygen chemical quencher., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Repurposing FDA-approved compounds could provide the fastest route to alleviate the burden of disease caused by flaviviruses. In this study, three fluoroquinolones, enoxacin, difloxacin and ciprofloxacin, curtailed replication of flaviviruses Zika (ZIKV), dengue (DENV), Langat (LGTV) and Modoc (MODV) in HEK-293 cells at low micromolar concentrations. Time-of-addition assays suggested that enoxacin suppressed ZIKV replication at an intermediate step in the virus life cycle, whereas ciprofloxacin and difloxacin had a wider window of efficacy. A129 mice infected with 1 × 10 5 plaque-forming units (pfu) ZIKV FSS13025 ( n = 20) or phosphate buffered saline (PBS) ( n = 11) on day 0 and treated with enoxacin at 10 mg/kg or 15 mg/kg or diluent orally twice daily on days 1-5 did not differ in weight change or virus titer in serum or brain. However, mice treated with enoxacin showed a significant, five-fold decrease in ZIKV titer in testes relative to controls. Mice infected with 1 × 10 2 pfu ZIKV ( n = 13) or PBS ( n = 13) on day 0 and treated with 15 mg/kg oral enoxacin or diluent twice daily pre-treatment and days 1-5 post-treatment also did not differ in weight and viral load in the serum, brain, and liver, but mice treated with enoxacin showed a significant, 2.5-fold decrease in ZIKV titer in testes relative to controls. ZIKV can be sexually transmitted, so reduction of titer in the testes by enoxacin should be further investigated.

The problems of parasite resistance, as well as the toxic residues to most of the commercially available antipiroplasmic drugs severely weaken their effective, curative, and environmental safe employment. Therefore, it is clear that the development of treatment options for piroplasmosis is vital for improving disease treatment and control. Ciprofloxacin is a broad-spectrum antibiotic that targets mainly the DNA replication machinery by inhibiting DNA gyrase and topoisomerase enzymes. As a result, ciprofloxacin is used for treating several bacterial and parasitic infections. In this study, the efficacy of 15 novel ciprofloxacin derivatives (NCD) that had been developed against drug-resistant Mycobacterium tuberculosis was evaluated against piroplasm parasite multiplication in vitro. The half-maximal inhibitory concentration (IC 50 ) values of the most effective five compounds of NCD (No. 3, 5, 10, 14, 15) on Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi were 32.9, 13.7, 14.9, and 30.9; 14.9, 25.8, 13.6, and 27.5; 34.9, 33.9, 21.1, and 22.3; 26.7, 28.3, 34.5, and 29.1; and 4.7, 26.6, 33.9, and 29.1 μM, respectively. Possible detrimental effects of tested NCD on host cells were assessed using mouse embryonic fibroblast (NIH/3T3) and Madin-Darby bovine kidney (MDBK) cell lines. Tested NCD did not suppress NIH/3T3 and MDBK cell viability, even at the highest concentration used (500 μM). Combination treatments of the identified most effective compounds of NCD/diminazene aceturate (DA), /atovaquone (AQ), and /clofazimine (CF) showed mainly synergistic and additive effects. The IC 50 values of NCD showed that they are promising future candidates against piroplasmosis. Further in vivo trials are required to evaluate the therapeutic potential of NCD.

Background/aim: This study aimed to investigate the effect of a new 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) ciprofloxacin-derivative on the proliferation and migration abilities of HeLa cells., Materials and Methods: Cell viability and morphological alterations were examined. Changes in migration were detected using wound healing and colony formation assays. Flow cytometry and western blotting were used to investigate the molecular mechanisms underlying this ciprofloxacin-derivative's action in HeLa cells., Results: The examined ciprofloxacin-derivative reduced viability of HeLa cells in a concentration-dependent manner and altered cellular morphology, indicating cell death. Furthermore, it significantly inhibited wound closure, even in a non-cytotoxic concentration, and reduced HeLa cell colony formation. In addition, apoptosis was increased probably through significant up-regulation of Bax protein expression and the generation of active cleaved caspase-3 protein., Conclusion: Our new derivative inhibits proliferation and induces apoptosis of HeLa cells. Furthermore, it suppressed the migration and colony formation abilities of HeLa cells. Therefore, it represents an attractive agent for drug development against cervical cancer based on its anti-metastatic effect., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The main objective of this study was to compare in vitro activities of a novel fluoroquinolone (FQ), UB-8902, with ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MOX) against Mycobacterium tuberculosis isolates. Eleven OFX-resistant and 11 drug-susceptible clinical isolates were studied. Individual minimum inhibitory concentrations of OFX, LFX, MOX, and UB-8902 were determined using Middlebrook 7H11 agar. The concentrations studied ranged from 0.125 to 128 μg/mL in twofold dilutions. UB-8902 was more active than LFX and similar to MOX for OFX-resistant M. tuberculosis isolates. In addition, UB-8902 and MOX showed equal activity against drug-susceptible isolates, both being more active than OFX and LFX. In conclusion, the new FQ, UB-8902, showed good activity against OFX-resistant isolates. Moreover, it showed better activity than OFX and LFX and was equivalent to MOX against FQ-susceptible clinical isolates. UB-8902 can be considered as a drug with potential antituberculous activity, similar to MOX.

Over expression of thymidine phosphorylase (TP) in various human tumors compared to normal healthy tissue is associated with progression of cancer and proliferation. The 2-deoxy-d-ribose is the final product of thymidine phosphorylase (TP) catalyzed reaction. Both TP and 2-deoxy-d-ribose are known to promote unwanted angiogenesis in cancerous cells. Discovery of potent inhibitors of thymidine phosphorylase (TP) can offer appropriate approach in cancer treatment. A series of ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 has been synthesized and characterized using spectroscopic techniques. Afterwards, inhibitory potential of synthesized ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 against thymidine phosphorylase enzyme was assessed. Out of these twelve analogs of ciprofloxacin nine analogues 3a-3c, 4a-4c, 5a-5b and 6 showed good inhibitory activity against thymidine phosphorylase. Inhibitory activity as presented by their IC 50 values was found in the range of 39.71 ± 1.13 to 161.89 ± 0.95 μM. The 7-deazaxanthine was used as a standard inhibitor with IC 50  = 37.82 ± 0.93 μM. Furthermore, the chick chorionic allantoic membrane (CAM) assay was used to investigate anti-angiogenic activity of the most active ciprofloxacin-based inhibitor 3b. To enlighten the important binding interactions of ciprofloxacin derivatives with target enzyme, the structure activity relationship and molecular docking studies of chosen ciprofloxacin analogues was discussed. Docking studies revealed key π-π stacking, π-cation and hydrogen bonding interactions of ciprofloxacin analogues with active site residues of thymidine phosphorylase enzyme., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A doubly porous microcomposite polyaniline/graphene oxide/octadecyl-bonded silica magnetite (PANI/GOx/C18-SiO 2 -Fe 3 O 4 ) alginate adsorbent was developed and employed to extract fluoroquinolones. The Fe 3 O 4 facilitated rapid and convenient for the separation of the adsorbent from sample solutions. The double porosity of the alginate hydrogel enhanced the surface area of the polyaniline coating. The developed method exhibited good linearity of 0.0010-50 μg L -1 for danofloxacin; 0.0050-50 μg L -1 for norfloxacin, ciprofloxacin and enrofloxacin; and 0.010-50 μg L -1 for sarafloxacin and difloxacin. The limits of detection were between 0.001 and 0.010 μg L -1 with RSD below 9.0%. The PANI/GOx/C18-SiO 2 -Fe 3 O 4 adsorbent was utilized to extract fluoroquinolones from honey, milk and egg samples and satisfactory extraction recoveries were achieved ranged from 80 to 98%. The developed adsorbent has good stability which can be reused up to 7 times, is simple to prepare and convenient to use for the extraction fluoroquinolones., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Herein, a surface-enhanced Raman scattering (SERS) strategy based on semiconducting substrate was exploited for detection of several antibiotic residues both in ultrapure water system and in actual water system. The as-prepared Ag-TiO 2 (Ag synchronously deposited and doped TiO 2 ) nanoparticle SERS-active substrate can achieve high sensitive SERS detection for difloxacin hydrochloride, ciprofloxacin, enrofloxacin, danofloxacin and enoxacin (five widely used quinolone antibiotics) in actual water samples, and the detection limits are as low as 4.36 × 10 -12 , 7.08 × 10 -11 , 3.94 × 10 -11 , 3.16 × 10 -11 and 3.15 × 10 -10 mol/L, respectively. These detection limits are far below the maximum of residue limit (3.01 × 10 -7 mol/L) stipulated by the European Union. And, the desirable quantitative relationships can be obtained in a wide concentration range. The recoveries of five antibiotic residues from spiked actual water samples are found to be more than 80.8% with the relative standard deviations between 2.1% and 4.7%. Even, the proposed SERS method can accurately distinguish every antibiotic species from a mixed antibiotic residue sample with multiple antibiotics. And, Ag-TiO 2 nanoparticles can also serve as an efficient photocatalyst for photocatalytic degradation of these antibiotic residues, which provides a multi-functional platform for synchronous determination and degradation of antibiotic residues in real environment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Of study is improving the results of treatment of patients with pyo-necrotic complications of diabetic foot syndrome by including the method of negative pressure wound treatment in the complex treatment program in combination with using of the combined antibacterial drug Cifran ST and immunocorrective therapy., Material and Methods: The results of examination and treatment of 184 patients with pyo-necrotic complications of the neuropathic form of diabetic foot syndrome were analyzed. According to choice of treatment methods in the postoperative period all patients were divided into two groups. In 95 patients (group I), iodine-containing ointments based on polyethylene glycol were used for local treatment of purulent foot wounds and standard systemic antibacterial therapy was performed. In 89 patients (group II), negative pressure wound treatment (NPWT) was used to treat wounds in the postoperative period. In addition to standard parenteral antimicrobial therapy, these patients also received an oral combined antibacterial drug Cifran ST and immunocorrective cytokine therapy (Leukinferon). The analysis of the dynamics of the wound process was carried out based on the clinical picture and the results of cytological, bacteriological and immunological studies of the wound exudate., Results: The presented strategy of complex treatment of pyo-necrotic complications of the neuropathic form of diabetic foot syndrome allowed group II patients to significantly reduce the degree of microbial contamination of wounds, to achieve a faster regression of the content of proinflammatory and inflammatory cytokines in the wound exudate, as well as to reduce the time of wound cleansing and the transition of the pyo-necrotic process to the reparative stage in comparison with group I patients. This allowed group II patients to reduce the time of plastic closure of the wound from 24.3±0.5 to 15.6±1.7 days, to avoid generalization of infection, death and high level amputation of the limb. At the same time, 11.6% of patients in group I had high level limb amputation due to generalization of infection. The mortality rate in group I was 5.3%., Conclusions: Adding of vacuum therapy of wounds, systemic antimicrobial therapy using the combined antibacterial drug Cifran ST and immunocorrective cytokine therapy in the complex treatment program for patients with neuropathic form of diabetic foot syndrome after radical surgical treatment of the pyo-necrotic lesion allows reducing the time of wound cleansing and the transition of the pyo-necrotic process to the reparative stage. On the other hand, this makes it possible for this category of patients to perform plastic closure of the wound at an earlier date, avoid generalization of infection and high level amputation of the limb.

Using the hologram quantitative structure-activity relationship (HQSAR) method, a quantitative model of the structure-activity relationship between the genotoxicity of quinolones towards gram-negative bacteria and structure of quinolones is constructed. A series of novel quinolones are designed, and 4 environmentally friendly quinolone derivatives are finally selected, because of their enhanced genotoxicity towards gram-negative/positive bacteria, decreased bioconcentration and increased photodegradability and biodegradability. The mechanisms underlying the genotoxicity of quinolones and its derivatives are analysed based on amino acid residues and molecular interactions. Three hydrophilic amino acids [arginine (ARG), asparagine (ASN) and aspartic acid (ASP)] play important roles in the antibacterial effects of quinolones. The introduction of highly hydrophilic groups into the C-7 position of amifloxacin (AMI) not only improved the stability of the AMI derivative-topoisomerase IV-DNA complex but also improved the antibacterial activities of AMI derivatives.

Burkholderia pseudomallei ( Bp ) and Burkholderia mallei ( Bm ) are Tier-1 Select Agents that cause melioidosis and glanders, respectively. These are highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis, and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened ∼220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis , a closely related BSL-2 surrogate. We identified 268 hits, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm Among these were a fluoroquinolone analog, which we named burkfloxacin (BFX), which potently inhibits growth of intracellular Burkholderia , and flucytosine (5-FC), an FDA-approved antifungal drug. We found that 5-FC blocks the intracellular life cycle at the point of type VI secretion system 5 (T6SS-5)-mediated cell-cell spread. Bacterial conversion of 5-FC to 5-fluorouracil and subsequently to fluorouridine monophosphate is required for potent and selective activity against intracellular Burkholderia In a murine model of fulminant respiratory melioidosis, treatment with BFX or 5-FC was significantly more effective than ceftazidime, the current antibiotic of choice, for improving survival and decreasing bacterial counts in major organs. Our results demonstrate the utility of cell-based phenotypic screening for Select Agent drug discovery and warrant the advancement of BFX and 5-FC as candidate therapeutics for melioidosis in humans., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

A nanooptosensor based on the fluorescence quenching of a composite probe was fabricated for the detection of sarafloxacin. The components of the nanocomposite fluorescent probe were a high affinity material of polydopamine polymer (PDA), a selective material of molecularly imprinted polymer (MIP), and optically sensitive quantum dots (QDs). The developed nanocomposite fluorescent probe exhibited excellent selectivity and sensitivity for sarafloxacin. The molecularly imprinted polymer had an imprinting factor (IF) of 8.18 and produced a probe that quenched fluorescence more effectively than a non-imprinted polymer (NIP) probe. The emission intensity of the MIP probe was linearly quenched by sarafloxacin over a range of 0.10 to 15.0 μg L -1 with a determination coefficient (R 2 ) of 0.9966. The developed nanooptosensor had a limit of detection of 0.05 μg L -1 . The optosensor detected sarafloxacin in chicken meat samples with recoveries ranging from 82.8 to 99.1% with an RSD below 3%. The found concentrations in spiked samples were compared well with recoveries obtained by HPLC method of detection. This developed nanooptosensor is simple to operate and cost-effective and the analytical procedure is rapid. Graphical abstract.

Tuberculosis is the deadliest infectious disease affecting humankind with a death toll of approximately 1.7 million people in 2016. The increasing prevalence of multidrug-resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (CPX) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent Mtb H37Rv strain in vitro. The small propionyl analogue 11 (MIC 90 1.6 μM; SI > 61) and the large cholesteryl hybrid 32 (MIC 90 2.0 μM; SI > 6) were the most active derivatives, comparable to CPX (MIC 90 1.8 μM). However, the slightly less active but non-cytotoxic para-fluorobenzyl hybrid 28 (MIC 90 3.7 μM; SI 27) was more selective toward bacteria than 32. Thus, the CPX derivatives 11 and 28 were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models., (© 2019 John Wiley & Sons A/S.)

The use of the heterologous competitive strategy has become a vital method to improve the sensitivity of ELISA. In this work, we prepared an anti-enrofloxacin (ENR) mAb with ENR-bovine serum albumin (BSA) as immunogen. The molecular descriptors of quinolones were then used to screen heterologous coating antigens for the detection of ENR based on an ensemble learning method to improve the sensitivity of the ELISA. Results indicated that 6 of the 7 selected heterologous competitive antigens could enhance the sensitivity of ELISA. The ELISA sensitivity for the detection of ENR with sarafloxacin-BSA as heterologous coating antigen was improved 10-fold (in PBS) and 6-fold (in milk) compared with that with ENR-BSA as homologous antigen. The strategy can effectively screen suitable heterologous competitive antigens to improve the sensitivity of ELISA, followed by preparation of mAb with no additional modification to the corresponding immunogen., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

99m Tc-ciprofloxacin scintigraphy is useful in the detection of gram-positive and gram-negative bacterial infections and also for differentiating the infection from aseptic inflammation. However, due to growing bacterial resistance to antibiotics, the 99m Tc-ciprofloxacin no longer can be effective in broad-spectrum infection imaging as it is gradually losing specificity. In this study, we are presenting our findings regarding the in vitro and in vivo susceptibility of 99m Tc-ciprofloxacin for multi-drug-resistant Staphylococcus aurous, Escherichia coli, and Pseudomonas aeruginosa bacterial strains which were isolated from clinical samples. The results of radiosynthesis of 99m Tc-ciprofloxacin showed more the 95% radiochemical purity and less than 5% radioactive impurities. In vitro 99m Tc-ciprofloxacin susceptibility test showed that E. coli offered more resistant to 99m Tc-ciprofloxacin as compared to S. aurous and P. aeruginosa. In vivo study using bacterial infection induced rabbit model also revealed lowest uptake by E. coli lesion. The T/NT values were obtained 1.96 ± 0.15 in the case of E. coli; 2.81 ± 0.51 in the case of S. aurous; and 2.32 ± 0.66 in the case of P. aeruginosa at 4 h post-injection. The SPECT infection imaging of S. aurous, E. coli, and P. aeruginosa bacterial infection induced rabbit models also indicated the clear accumulation in S. aurous and P. aeruginosa lesions while negligible uptake by E. coli lesion further verify the in vitro and in vivo susceptibility profile. On the bases of the results obtained, the 99m Tc-ciprofloxacin showed selective and poor broad spectrum SPECT infection imaging.

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

This work determined the potency of hexyl-ciprofloxacin molecules that reversibly interact with gold nanoparticles (AuNPs) passivated with 11-mercaptoundecanoic acid (MUA) on Escherichia coli cells. For this, partition of modified antibiotic between different compartments of the gold colloid was determined using analytical techniques. First, concentration of hexyl-ciprofloxacin was determined in the continuous phase of the colloid. Subsequently, the colloid was exposed to a volume of organic immiscible solvent and concentration of the transferred molecules was determined in the organic phase. Comparison of the amount of hexyl-ciprofloxacin in each phase revealed that interaction between molecules and nanoparticles was reversible. Later, this work determined the potency of a population of hexyl-ciprofloxacin molecules contained in a volume of the colloid, and the potency of other population of molecules that only interact with the continuous phase of the colloid. The absolute difference between these two values was proportional to the potency of a number of molecules that interact with the nanoparticles of the colloid.

Background: Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335)., Methods: Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues., Results: Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages., Conclusions: 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.

Pharmacokinetics of difloxacin (DF), a fluoroquinolone antibiotic, were investigated in Japanese quails (Coturnix japonica) after a single intravenous (IV) and oral (PO) administration of 10 mg/kg bodyweight. Plasma concentration profiles of DF were analyzed by a compartmental pharmacokinetic method. Following IV injection, the plasma concentration vs time profile was best described by a two-compartment open model. Elimination half-life (t 1/2β ), total body clearance (Cl tot ), volume of distribution at steady state (V dss ) and mean residence time (MRT) of DF were 5.45 ± 0.14 h, 0.22 ± 0.01 L/kg/h, 1.54 ± 0.06 L/kg and 6.92 ± 0.19 h, respectively. Following PO administration, DF was rapidly absorbed, with peak plasma concentration (C max ) of 3.67 μg/mL attained at 1.90 h (T max ) after administration. Absorption half-life (t 1/2ab ), elimination half-life (t 1/2el ), mean absorption time (MAT) were 0.5 h, 5.26 h and 1.11 h, respectively. The bioavailability (F) following PO administration of DF was high (84.40%). For a successful clinical effect of DF in quails, a multiple dosage regimen of 10 mg/kg bodyweight, administered orally every 24 h is recommended to maintain effective plasma concentrations with bacterial infections, in which MIC90 is <0.2 μg/mL., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Micellar liquid chromatography - fluorescence detection was used to determine the antibiotics flumequine, marbofloxacin, difloxacin, and sarafloxacin in porcine, bovine, poultry, ovine, caprine, rabbit, and equine meat, to verify compliance with EU Regulation 37/2010 with regard to the occurrence of veterinary drugs in food., Results: The analytes were isolated from the matrix by ultrasonication-assisted leaching in a micellar solution, and the supernatant was filtered and directly injected. The fluoroquinolones were resolved in < 19 min using a C18 column, with an isocratic mobile phase of 0.05 mol L -1 sodium dodecyl sulfate - 8% 1-butanol - 0.5% triethylamine buffered at pH 3. The limits of quantification (0.01-0.05 mg kg -1 ) were below the maximum residue limits (0.15-0.4 mg kg -1 ). The method was validated by EU Commission Decision 2002/657/EC guidelines., Conclusion: The method shows practical advantages such as simplicity, low cost, eco-friendliness, safety, and applicability for routine analysis, and is useful for surveillance programs. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

Affecting the vast majority of human beings, dental caries is a premier concern of worldwide dental health. As the most commonly used restorative material to treat dental caries, resin-based composites (RBCs) lack antibacterial properties leading to quite limited restoration lifetimes. The objective of this study is to develop a polymer-antibiotic conjugate (PAC) as an effective antibacterial additive for RBCs. A monomer-antibiotic conjugate (MAC) with significant solubility was prepared by an esterification reaction of tert-butyloxycarbonyl (Boc)-protected ciprofloxacin (Cip) and 2-hydroxyethyl methacrylate (HEMA). The Cip-containing PAC with well-controlled molecular weight and composition was synthesized by reversible addition-fragmentation chain transfer (RAFT) copolymerization of the MAC with HEMA (1 : 3 molar ratio), followed by the removal of Boc from the resulting copolymer. The antibacterial dental resin was then prepared by incorporating the PAC into a commercial resin, and their properties and antibacterial performance against Streptococcus mutans were tested. In vitro experiments revealed a very slow release of Cip, which resulted in significant killing effectiveness against Streptococcus mutans nonetheless, as observed through zone of inhibition assessment and SEM imaging. The promising antibacterial properties of these resins indicate that incorporating a PAC as an additive is a valid strategy to generate antibacterial materials for dental applications.

The inherent bioinertness and potential bacterial infection risk are the two leading causes for Ti implant failure. To improve osseointegration and antibiosis, in this work, a novel antimicrobial osteogenic growth peptide was first synthesized by conjugating osteogenic growth peptide (OGP) and ciprofloxacin (CIP). Then, the synthetic antimicrobial peptide was immobilized onto Ti implant surface for chemoselective binding via the amide reaction. Thereafter, the capabilities of modified Ti implant on osseointegration and antibiosis were measured with cell experiments and antimicrobial activity in vitro. The results showed that antimicrobial osteogenic growth peptide (OGP-CIP) was successfully prepared and grafted onto Ti implant surface. Moreover, the antimicrobial peptide-modified Ti implants could promote osteoblasts spreading and osteodifferentiation compared with unmodified Ti substrates. Meanwhile, in vitro bacteria studies (Staphylococcus aureus and Escherichia coli) proved that the antibacterial property of antimicrobial peptide functionalized Ti implant was improved obviously. The method used in this work is a feasible and promising strategy to win the race against invading bacteria and accelerate bone integration in orthopedic implantation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3021-3033, 2018., (© 2018 Wiley Periodicals, Inc.)

Two new 1,3,4-thiadiazole derivatives of ibuprofen and ciprofloxacin namely {(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-amine)} 1 and {(3-(5-amino-1,3,4-thiadiazol-2-yl)-1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)quinolin-4(1H)-one)} 2 were synthesized and characterized by spectroscopic and elemental analysis. DFT and molecular docking were done initially for theoretical binding possibilities of the investigated compounds. In vitro DNA binding investigations were carried out with UV-visible spectroscopic, fluorescence spectroscopic, cyclic voltammetric (CV) experiments under physiological conditions of the stomach (4.7) and blood (7.4) pH and at normal body temperature (37 °C). Both theoretical and experimental results suggested spontaneous and significant intercalative binding of the compounds with DNA. Kinetic and thermodynamic parameters (K b , ΔG) were evaluated greater for compound 2 which showed comparatively more binding and more spontaneity of 2 than 1 to bind with DNA at both pH values. Binding site sizes were found greater (n > 1) and revealed the possibility of other sites for interactions along with intercalation. Overall results for DNA binding were found more significant for 2 at Stomach (4.7) pH. Viscometric studies further verified intercalation as a prominent binding mode for both compounds. IC 50 values obtained from human hepatocellular carcinoma (Huh-7) cell line studies revealed 2 as potent anticancer agent than 1 as value found 25.75 μM (lesser than 50 μM). Theoretical and experimental DNA binding studies showed good correlation with cancer cell (Huh-7) line activity of 1 and 2 and further suggested that these compounds could act as potential anti-cancer drug candidates., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Fluoroquinolones (FQs) are compounds of major interest with broad antimicrobial activities against community and hospital-acquired infections such as respiratory tract infections (nosocomial pneumonia, chronic bronchitis and tuberculosis), skin and soft tissue infections, bone and joint infections, intra-abdominal infections and sexually transmitted diseases. This broad range of activities along with favorable pharmacokinetic and low toxicity introduced this class of compounds as important antimicrobial chemotherapy agents. The rapid increase in prevalence of FQs resistant microbes in environment motivated medicinal chemists to discover new quinolone-based compounds with potent activities against Gram-positive bacteria., Methods: The designed compounds were prepared through the two-component reaction between aromatic α-haloketones or α-halooximes and sarafloxacin in the presence of NaHCO 3 in DMF, affording the corresponding N-[2-(aryl-3-yl) ethyl] piperazinyl quinolone derivatives in good yields. All synthesized compounds were evaluated for antibacterial activities against Gram-positive [Staphylococcus aureus ATCC 6538p, Micrococcus luteus, ATCC 1110, Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633] and Gram-negative [Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 10031 Pseudomonas aeruginosa ATCC 9027 and Serratia marcescens PTCC 1111] bacteria., Results: The antibacterial activities of 24 new compounds were reported as MIC values in comparison to sarafloxacin. The most active compound, 4 g, exhibited similar inhibitory activity against Gram-positive bacteria including S. aureus, S. epidermidis and B. subtilis compared to positive control. Furthermore, benzyloxime incorporated derivatives (4 s-4x) showed poor activity against all tested strains, except 4x., Conclusion: The obtained results indicated that the synthesized compounds containing substituted piperazine moiety at the C-7 position displayed same or weak inhibitory activities compared to sarafloxacin. Graphical abstract ᅟ.

A new class of 1-[(1R,2S)-2-fluorocyclopropyl]ciprofloxacin (CPFX)-1,2,4-triazole-5(4H)-thione hybrids 6a - 6o was designed, synthesized and evaluated for their in vitro antibacterial activities against a panel of clinically important drug-sensitive and drug-resistant Gram-positive and Gram-negative pathogens. Our results revealed that all hybrids 6a - 6o had great potency against the tested strains, especially Gram-negative pathogens. The synthesized hybrids were more potent than the parent 1-[(1R,2S)-2-fluorocyclopropyl]CPFX (1) and comparable to CPFX and levofloxacin against the majority of the tested pathogens, worth to be further investigated., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

A novel series of ciprofloxacin-dithiocarbamate hybrids 7a - 7l were designed, synthesized, and evaluated against Gram-positive and Gram-negative bacteria. A significant part of the title compounds showed considerable antibacterial activity against Gram-positive species. The most potent compound against Gram-positive bacteria was 2-chloro derivative 7h and the most potent derivative against Gram-negative bacteria was 3-chloro compound 7i. In vitro antibacterial evaluation of compound 7h against clinically isolated bacteria methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) showed that this compound acted better than ciprofloxacin against the latter bacteria. Docking study of compound 7h in the active site of S. aureus DNA gyrase revealed that this ciprofloxacin-dithiocarbamate derivative interacted with the main components of the active site of the enzyme., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

The impressive ability of the fungus Xylaria longipes to transform the highly persistent fluoroquinolone ciprofloxacin into microbiologically less active degradation products was demonstrated. Fluoroquinolones are used extensively in both human and veterinary medicine. Poor metabolization and high chemical stability of these synthetic antibiotics led to their presence in several environmental compartments. This undesirable behavior may promote the spread of resistance mechanisms due to concomitant exposure to bacteria. Therefore, the biotransformation of ciprofloxacin, one of the most prescribed fluoroquinolones in human medicine, by the ascomycetous soft rot fungus X. longipes was investigated in detail. Submerged cultivation of the fungus allowed for high-yield formation of four biotransformation products. These compounds were subsequently purified by preparative high-performance liquid chromatography. Applying accurate mass spectrometry and nuclear magnetic resonance spectroscopy, desethylene-ciprofloxacin, desethylene-N-acetyl-ciprofloxacin, N-formyl-ciprofloxacin and N-acetyl-ciprofloxacin were unambiguously identified. N-acetylation and N-formylation of the drug led to a 75-88% reduction of the initial antibacterial activity, whereas a breakdown of the piperazine substituent resulted in almost inactive products. These findings suggest an important role in the inactivation and degradation of this and other synthetic compounds in the environment.

Twelve novel propylene-tethered ciprofloxacin-isatin hybrids 3a-f and 4a-f were designed, synthesized and characterized by MS, HRMS, 1 H NMR and 13 C NMR. All hybrids were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and mycobacterial pathogens, cytotoxicity in VERO cell line as well as metabolic stability and in vivo pharmacokinetic (PK) properties. The preliminary results indicated that all mono-isatin-ciprofloxacin hybrids exhibited excellent antibacterial activities with MIC ranging from ≤0.03 to 0.5 μg/mL against most of the tested strains. In particular, ciprofloxacin-isatin hybrid 3d was highly potent against all tested Gram-positive and Gram-negative strains including clinically important drug-resistant pathogens, which was comparable to or more potent than the parent ciprofloxacin and reference levofloxacin. Whereas, conjugate 3b (MIC: 0.10 and 0.5 μg/mL) was 4- and 8-fold more active than ciprofloxacin (MIC: 0.78 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H 37 Rv, and 4->256 times more potent than the three references ciprofloxacin (MIC: 2.0 μg/mL), rifampicin (MIC: 32 μg/mL) and isoniazid (>128 μg/mL) against MDR-TB. Both hybrid 3b and 3d with low cytotoxicity (CC 50 : 64 and 256 μg/mL) also showed acceptable metabolic stability and in vivo PK properties, could act as leads for further optimization., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (P X s) for noneliminating tissues were calculated according to the area method, while the P X s for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra-label manner using the PBPK modeling., (© 2018 John Wiley & Sons Ltd.)

The pharmacokinetics of orbifloxacin was studied after a single dose (7.5 mg/kg) of intravenous or intramuscular administration to crucian carp (Carassius auratus) reared in freshwater at 25°C. Plasma samples were collected from six fish per sampling point. Orbifloxacin concentrations were determined by high-performance liquid chromatography with a 0.02 μg/ml limit of detection, then were subjected to noncompartmental analysis. After intravenous injection, initial concentration of 5.83 μg/ml, apparent elimination rate constant (λ z ) of 0.039 hr -1 , apparent elimination half-life (T 1/2λz ) of 17.90 hr, systemic total body clearance (Cl) of 75.47 ml hr -1  kg -1 , volume of distribution (Vz) of 1,948.76 ml/kg, and volume of distribution at steady-state (Vss) of 1,863.97 ml/kg were determined, respectively. While after intramuscular administration, the λ z , T 1/2λz , mean absorption time (MAT), absorption half-life (T 1/2ka ), and bioavailability were determined as 0.027 hr -1 , 25.69, 10.26, 7.11 hr, and 96.46%, respectively, while the peak concentration was observed as 3.11 ± 0.06 μg/ml at 2.0 hr. It was shown that orbifloxacin was completely but relatively slowly absorbed, extensively distributed, and slowly eliminated in crucian carp, and an orbifloxacin dosage of 10 mg/kg administered intravenously or intramuscularly would be expected to successfully treat crucian carp infected by strains with MIC values ≤0.5 μg/ml., (© 2018 John Wiley & Sons Ltd.)

In this paper, we present a comparative study on the cytotoxic mode of action of copper(I) and copper(II) complexes with phosphine derivatives of fluoroquinolone antibiotics (ciprofloxacin HCp and norfloxacin HNr). The in vitro cytotoxic activity of four new compounds was tested against two selected cancer cell lines. All complexes exhibited much better cytotoxicity against both cell lines than unmodified fluoroquinolone antibiotics, their phosphines (PCp, PNr), chalcogenide derivatives (oxides: OPCp, OPNr; sulfides: SPCp, SPNr and selenides: SePCp, SePNr) and previously described by us complexes with phosphines derived from different fluoroquinolones: lomefloxacin (HLm) and sparfloxacin (HSf) as well as cisplatin. Apoptosis, observed at a great predominance, was induced by all studied complexes. Importantly, it was concluded that coordination compounds with Cu(I) ion ([Cu I -PNr] and [Cu I -PCp]) were much more active than those with Cu(II) ion ([OPNr-Cu II ], [OPCp-Cu II ]), even though the highest efficacy to produce reactive oxygen species, participating in overall cytotoxicity, was proved for copper(II) complexes among all studied compounds. Herein, we discuss not only results obtained for copper(I)/(II) complexes with phosphines derived from HNr and HCp but we also compare them to previously described data for complexes with HLm and HSf derivatives. This is the first insight into a structure-activity relationship of copper complexes with phosphine derivatives of fluoroquinolone antibiotics., (Copyright © 2018 Elsevier Inc. All rights reserved.)