1,8-naphthyridine derivatives: an updated review on recent advancements of their myriad biological activities.

Among all nitrogen-containing heterocycles, the 1,8-naphthyridine scaffold has recently gained an immense amount of curiosity from numerous researchers across fields of medicinal chemistry and drug discovery. This new attention can be ascribed to its versatility of synthesis, its reactiveness and the variety of biological activities it has exhibited. Over the past half-decade, numerous diverse biological evaluations have been conducted on 1,8-naphthyridine and its derivatives in a quest to unravel novel pharmacological facets to this scaffold. Its potency to treat neurodegenerative and immunomodulatory disorders, along with its anti-HIV, antidepressant and antioxidant properties, has enticed researchers to look beyond its broad-spectrum activities, providing further scope for exploration. This review is a consolidated update of previous works on 1,8-naphthyridines and their analogs, focusing on the past 5 years.

Identification of a Novel TAR RNA-Binding Protein 2 Modulator with Potential Therapeutic Activity against Hepatocellular Carcinoma.

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.

Modulating microRNA Processing: Enoxacin, the Progenitor of a New Class of Drugs.

The RNA interference (RNAi) process encompasses the cellular mechanisms by which short-noncoding RNAs posttranscriptionally modulate gene expression. First discovered in 1998, today RNAi represents the foundation underlying complex biological mechanisms that are dysregulated in many diseases. MicroRNAs are effector molecules of gene silencing in RNAi, and their modulation can lead to a wide response in cells. Enoxacin was reported as the first and unique small-molecule enhancer of microRNA (SMER) maturation. Herein, the biological activity of enoxacin as SMER is discussed to shed light on its innovative mode of action, its potential in treating different diseases, and the feasibility of using enoxacin as a chemical template for inspiring medicinal chemists. We debate its mechanism of action at the molecular level and the possible impact on future ligand and/or structure-guided chemical optimizations, as well as opportunities and drawbacks associated with the development of quinolones such as SMERs.

Chlorination of enoxacin (ENO) in the drinking water distribution system: Degradation, byproducts, and toxicity.

Chlorine is widely used as a drinking water disinfectant to ensure water security. However, the transformation mechanisms of its degradation of emerging pollutants within the water distribution system (WDS) is insufficiently understood. Thus, the kinetics, degradation byproducts, and toxicity of the chlorination of enoxacin (ENO, a type of emerging pollutant) were explored in a pilot-scale WDS for the first time. It was found that the chlorination rate of ENO was higher in deionized water (DW) than in the pilot-scale WDS, and the degradation followed second-order kinetics in DW. The degradation efficiency was found to be sensitive to pH, and was highest at a pH of 7.4. The chlorination rate of ENO increased with increasing temperature in both DW and WDS. For different pipe materials, the relative performance of ENO chlorination efficiency followed the order of steel pipe > ductile iron pipe > polyethylene (PE) pipe. Seven intermediates were identified during ENO chlorination, and the primary oxidation reaction involved the cleavage of the piperazine group. Finally, it was found that the potential for chlorine toxicity in treated drinking water in the presence of ENO is higher than it is without this pollutant.

Immobilization of type I collagen/hyaluronic acid multilayer coating on enoxacin loaded titania nanotubes for improved osteogenesis and osseointegration in ovariectomized rats.

Titania nanotubes (Ti-NTs) have been proven to be good drug carriers and can release drugs efficiently around implants. Enoxacin (EN) is a broad-spectrum antibiotic that has the ability of anti-osteoclastogenesis. Immobilization of extracellular matrix components on the surface of the material can greatly enhance the biological activity of the implant and slow down the release rate of the drug in Ti-NTs. In the present study, a material system that provided uniform drug release, promoted osteogenesis, and inhibited osteoclast was designed and developed. Scanning electron microscopy, X-ray photoelectron spectroscopy, and water contact angle measurements were used for material surface characterization. Enoxacin release was detected by high performance liquid chromatography. Alkaline phosphatase and Alizarin Red staining were used to evaluate the osteogenic differentiation of rat bone marrow mesenchymal stem cells. Tartrate-resistant acid phosphatase staining and bone absorption assay were applied to osteoclastogenesis experiments. A drug delivery system based on Ti-NTs and type I collagen /hyaluronic acid multilayer coating (Ti-NT+EN+Col/HyA) with predominant biocompatibility, osteogenic property, and anti-osteoclastogenesis ability was successfully constructed. These excellent biological properties were further validated in an ovariectomized rat model. The results of the study indicate that Ti-NT+EN+Col/HyA is a potential material for future orthopedic implants.

Click Quantitative Mass Spectrometry Identifies PIWIL3 as a Mechanistic Target of RNA Interference Activator Enoxacin in Cancer Cells.

Enoxacin is a small molecule that stimulates RNA interference (RNAi) and acts as a growth inhibitor selectively in cancer but not in untransformed cells. Here, we used alkenox, a clickable enoxacin surrogate, coupled with quantitative mass spectrometry, to identify PIWIL3 as a mechanistic target of enoxacin. PIWIL3 is an Argonaute protein of the PIWI subfamily that is mainly expressed in the germline and that mediates RNAi through piRNAs. Our results suggest that cancer cells re-express PIWIL3 to repress RNAi through miRNAs and thus open a new opportunity for cancer-specific targeting.

Covalent Immobilization of Enoxacin onto Titanium Implant Surfaces for Inhibiting Multiple Bacterial Species Infection and In Vivo Methicillin-Resistant Staphylococcus aureus Infection Prophylaxis.

Infection is one of the most important causes of titanium implant failure in vivo A developing prophylactic method involves the immobilization of antibiotics, especially vancomycin, onto the surface of the titanium implant. However, these methods have a limited effect in curbing multiple bacterial infections due to antibiotic specificity. In the current study, enoxacin was covalently bound to an amine-functionalized Ti surface by use of a polyethylene glycol (PEG) spacer, and the bactericidal effectiveness was investigated in vitro and in vivo The titanium surface was amine functionalized with 3-aminopropyltriethoxysilane (APTES), through which PEG spacer molecules were covalently immobilized onto the titanium, and then the enoxacin was covalently bound to the PEG, which was confirmed by X-ray photoelectron spectrometry (XPS). A spread plate assay, confocal laser scanning microscopy (CLSM), and scanning electron microscopy (SEM) were used to characterize the antimicrobial activity. For the in vivo study, Ti implants were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and implanted into the femoral medullary cavity of rats. The degree of infection was assessed by radiography, micro-computed tomography, and determination of the counts of adherent bacteria 3 weeks after surgery. Our data demonstrate that the enoxacin-modified PEGylated Ti surface effectively prevented bacterial colonization without compromising cell viability, adhesion, or proliferation in vitro Furthermore, it prevented MRSA infection of the Ti implants in vivo Taken together, our results demonstrate that the use of enoxacin-modified Ti is a potential approach to the alleviation of infections of Ti implants by multiple bacterial species.

Europium Luminescence Used for Logic Gate and Ions Sensing with Enoxacin As the Antenna.

Luminescent lanthanide ion complexes have received increasing attention because of their unique optical properties. Herein, we discovered that the luminescence of europium(III) (Eu(3+)) could be regulated by Ag(+) and SCN(-) in seconds with enoxacin (ENX) as the antenna. Under given conditions, only the simultaneous introduction of Ag(+) and SCN(-) could remarkably enhance the luminescence intensity of Eu(3+)-ENX complexes. This phenomenon has been exploited to design an "AND" logic gate and specific luminescence turn-on assays for sensitively sensing Ag(+) and SCN(-) for the first time. Furthermore, the addition of S(2-) resulted in efficient luminescence quenching of the Eu(3+)/ENX/Ag(+)/SCN(-) system due to the strong affinity between Ag(+) and S(2-). Thus, a new luminescent sensing platform for S(2-) was established, which exhibited excellent selectivity and high sensitivity. S(2-) could be detected within the concentration range of 100 nM to 12.5 µM with a detection limit of 60 nM. Such sensing system features simplicity, rapidity, and flexibility. Moreover, this proposed Eu(3+)-based luminescent assay could be successfully applied in the real environmental water sample analysis.

Degradation of enoxacin antibiotic by the electro-Fenton process: Optimization, biodegradability improvement and degradation mechanism.

This study aims to investigate the effectiveness of the electro-Fenton process on the removal of a second generation of fluoroquinolone, enoxacin. The electrochemical reactor involved a carbon-felt cathode and a platinum anode. The influence of some experimental parameters, namely the initial enoxacin concentration, the applied current intensity and the Fe(II) amount, was examined. The degradation of the target molecule was accompanied by an increase of the biodegradability, assessed from the BOD5 on COD ratio, which increased from 0 before treatment until 0.5 after 180 min of electrolysis at 50 mg L(-1) initial enoxacin concentration, 0.2 mmol L(-1) Fe(II) concentration and 300 mA applied current intensity. TOC and COD time-courses were also evaluated during electrolysis and reached maximum residual yields of 54% and 43% after 120 min of treatment, respectively. Moreover, a simultaneous generation of inorganic ions (fluorides, ammonium and nitrates) were observed and 3 short chain carboxylic acids (formic, acetic and oxalic acids) were identified and monitored during 180 min of electrolysis. By-products were identified according to UPLC-MS/MS results and a degradation pathway was proposed.

Sensitive determination of enoxacin in pharmaceutical formulations by its quench effect on the fluorescence of glutathione-capped CdTe quantum dots.

A sensitive and simple method for the determination of enoxacin (ENX) was developed based on the fluorescence quenching effect of ENX for glutathione (GSH)-capped CdTe quantum dots (QDs). Under optimum conditions, a good linear relationship was obtained from 4.333 × 10(-9) mol⋅L(-1) to 1.4 × 10(-5) mol⋅L(-1) with a correlation coefficient (R) of 0.9987, and the detection limit (3σ/K) was 1.313 × 10(-9) mol⋅L(-1). The corresponding mechanism has been proposed on the basis of electron transfer supported by ultraviolet-visible (UV) light absorption, fluorescence spectroscopy, and the measurement of fluorescence lifetime. The method has been applied to the determination of ENX in pharmaceutical formulations (enoxacin gluconate injections and commercial tablets) with satisfactory results. The proposed method manifested several advantages such as high sensitivity, short analysis time, low cost and ease of operation.

Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.

An interaction between the B2 subunit of vacuolar H(+)-ATPase (V-ATPase) and microfilaments is required for osteoclast bone resorption. An atomic homology model of the actin binding site on B2 was generated and molecular docking simulations were performed. Enoxacin, a fluoroquinolone antibiotic, was identified and in vitro testing demonstrated that enoxacin blocked binding between purified B2 and microfilaments. Enoxacin dose dependently reduced the number of osteoclasts differentiating in mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D(3), as well as markers of osteoclast activity, and the number of resorption lacunae formed on bone slices. Enoxacin inhibited osteoclast formation at concentrations where osteoblast formation was not altered. In summary, enoxacin is a novel small molecule inhibitor of osteoclast bone resorption that acts by an unique mechanism and is therefore an attractive lead molecule for the development of a new class of antiosteoclastic agents.

Dysprosium-sensitized chemiluminescence system for the determination of enoxacin in pharmaceutical preparations and biological fluids with flow-injection sampling.

A novel trivalence dysprosium(Dy(3+))-sensitized chemiluminescence method was developed for the first time for the determination of enoxacin (ENX) using flow-injection sampling based on the chemiluminescence (CL) associated with the reaction of the Dy(3+)-cerium(Ce(IV))-S(2)O(3) (2-)-ENX system and the Dy(3+)-MnO(4) (-) S(2)O(3) (2-)-ENX system. The analytical conditions for CL emission were investigated and optimized. The relationship between the CL intensity of ENX and its concentration has good linearity, with a correlation coefficient of 0.9984-0.9994. The limit of detection (LOD, 3sigma) was 0.20 ng/mL for the Dy(3+)-ENX-S(2)O(3)(2-)-Ce(IV)-H(2)SO(4) system and 0.22 ng/mL for the Dy(3+)-ENX-S(2)O(3)(2-)-MnO(4) (-)-HNO(3) system. The relative standard deviation (RSD, n = 11) was 1.8% for 11 determinations of 60 ng/mL ENX. The proposed method was applied to the analysis of ENX in injections, serum and urine samples with a recovery of 98%-105%. A possible mechanism for this sensitized CL reaction is discussed by comparing the CL spectra with the fluorescence emission spectra. The proposed method represents a wide linear range, high sensitivity and accuracy, and can be used for the routine determination of ENX in pharmaceutical preparations and biological fluids.

Formation of secondary triplet species after excitation of fluoroquinolones in the presence of relatively strong bases.

Laser flash photolysis of 7-(piperazin-1-yl) fluoroquinolones leads to the formation of a triplet excited state (3A*) at the end of the pulse (lambdamax 520, 610, and 620 nm for enoxacin, ciprofloxacin, and norfloxacin, respectively). Phosphate and bicarbonate buffers react with 3A* to form a secondary triplet (3B*, reaction rates (0.8-9.9) x 108 M-1 s-1), whose T-T absorption is red-shifted (lambdamax 670 nm for enoxacin, 700 nm for ciprofloxacin and norfloxacin). The formation of a secondary triplet is not a common process and disagrees with previous work suggesting that electron transfer occurs between phosphate buffer and the primary triplet excited state with the formation of the anion radical of the fluoroquinolone (FQ.-). We have shown that the FQ.- transient absorption spectrum is quite distinct from that of 3B*. The photophysical characteristics of 3B* have been determined by energy transfer to naproxen, and it has been found that its energy is lower than that of 3A*.

Determination of enoxacin using Tb composite nanoparticles sensitized luminescence method.

In our study, terbium-acetylacetone (Tb-acac) composite nanoparticles have been prepared under vigorous ultrasonic irradiation. The nanoparticles are water soluble, stable and have extremely narrow emission bands and high internal quantum efficiencies. They were used as fluorescence probes in the determination of enoxacin (Enox) based on the fluorescence enhancement of nanoparticles through fluorescence resonance energy transfer (FRET). The influence of buffer solution on the fluorescence intensity was investigated. Under the optimum conditions, the fluorescence intensity of the Tb-acac-Enox system is linearly proportional to the Enox concentration in the Enox concentration range of 2 x 10(-7)-1 x 10(-4) M. The correlation coefficient for the calibration curve was 0.9976. The limit of detection as defined by IUPAC, C (LOD) = 3S (b)/m (where S (b) is the standard deviation of the blank signals and m is the slope of the calibration graph) was found to be 3 x 10(-8) M. The relative standard deviation (RSD) for six repeated measurements of 1 x 10(-4) M Enox was 1.35%. The method was applied to the determination of Enox in pharmaceutical formulation and recovery results were obtained from urine samples.

In vitro availability studies of enoxacin in presence of H2 receptor antagonists.

Enoxacin is a second-generation quinolone with increased antibacterial activity both in potency as well as in terms of broad spectrum against a wide range of clinically important pathogens over the first generation quinolones and produces its effect by inhibiting bacterial enzyme DNA gyrase. There are a number of drug interactions reported for enoxacin. On the other hand H2-receptor antagonists block gastric acid secretion and some cardiovascular effects of histamine. As the later drugs are used for a long-term therapy, they may be coadministered with other drugs. In present study in vitro release of enoxacin in presence of cimetidine, ranitidine and famotidine has been studied on a B.P. 2003 dissolution test apparatus and compared with the availability of enoxacin and H2-receptor antagonists alone. The interacting drugs were analyzed spectrophotometrically. These studies were carried out in simulated gastric juice, simulating empty stomach, simulated intestinal juice (pH 9) and buffers of pH 7.4 simulating blood pH at 37 degrees C. In order to support these interaction studies, the effect of H2-receptor antagonists on the antibacterial efficacy (MIC) of enoxacin was also studied by turbidity method and compared with parent drug against Staphylococcus aureus, Streptococcus pyogens, Streptococcus pneumoniae, Enterococcus, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Bacillus subtilis. On the basis of these results, it is suggested that enoxacin should be coadministered with care along with H2-receptor antagonists especially in case of ranitidine, although chances of adverse reactions are rare but decrease in MIC of enoxacin may result in delayed effect or require prolonged use of the drug.

A batch chemiluminescence determination of enoxacin using a tris-(1,10-phenanthroline)ruthenium(II)-cerium(IV) system.

A batch type chemiluminescence (CL) determination of enoxacin is described. In this work, it was observed that enoxacin could enhance the chemiluminescence (CL) emission Ru(phen)3(2+)-Ce(IV) system and this enhancement effect was dependent on the concentration of enoxacin, based on which, CL system was established for the determination of enoxacin. Under the optimum experimental conditions, the linear range and detection limit are 0.6406-64.06 microg/ml and 0.0210 microg/ml, respectively. The R.S.D. is 1.75%. (n = 10). The proposed method has been applied to detect the content of enoxacin in pharmaceutical formulation and human serum with satisfactory results. The possible mechanism of the CL reaction was discussed.

A new approach to quantitative NMR: fluoroquinolones analysis by evaluating the chemical shift displacements.

Quantitative NMR spectroscopy is always an attractive goal as the identity and quantity could be simultaneously determined. Although significant advancements have been achieved in this field it is common that all reported quantitative NMR methods perform the analysis by utilizing the average integral intensities of selected signals. During the calculation of the area under NMR peaks several response problems can occur which should always be treated carefully to overcome inaccuracies. In the method proposed in this work the quantitative information is obtained utilizing the measurement of selected protons chemical shift displacements which is a quite straightforward and highly reproducible process. The (1)H NMR spectra of multiple fluoroquinolone (FQ) solutions revealed that the chemical shifts of protons, especially the aromatic ones, were concentration dependent for all tested compounds, as a result of extensive self-association phenomena. In the present work a novel methodology is described for the quantitation of several FQs based on this dependence. The proposed method was applied to Ciprofloxacin solutions over a wide range of concentrations. Evaluation of the obtained data presented acceptable characteristics regarding accuracy, precision, and robustness. The applicability limitations of this method were found to be posed by current instrumentation, mainly by the magnetic field frequency e.g. the slope of the response function achieved with a 400MHz instrument was twice the one achieved at 200MHz. The pH effect was negligible from pD 2.5 to 5.5. The phenomenon appeared in a pattern that can be applied for a plethora of drug categories revealing self-association phenomena in a range of concentration determined by the magnet strength of the instrument.

T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity.

BACKGROUND: Quinolones are widely used, broad spectrum antibiotics that can induce immediate- and delayed-type hypersensitivity reactions, presumably either IgE or T cell mediated, in about 2-3% of treated patients. OBJECTIVE: To better understand how T cells interact with quinolones, we analysed six patients with delayed hypersensitivity reactions to ciprofloxacin (CPFX), norfloxacin (NRFX) or moxifloxacin (MXFX). METHODS: We confirmed the involvement of T cells in vivo by patch test and in vitro by means of the lymphocyte proliferation test (LTT). The nature of the drug-T cell interaction as well as the cross-reactivity with other quinolones were investigated through the generation and analysis (flow cytometry and proliferation assays) of quinolone-specific T cell clones (TCC). RESULTS: The LTT confirmed the involvement of T cells because peripheral blood mononuclear cells (PBMC) mounted an enhanced in vitro proliferative response to CPFX and/or NRFX or MXFX in all patients. Patch tests were positive after 24 and 48 h in three out of the six patients. From two patients, CPFX- and MXFX-specific CD4(+)/CD8(+) T cell receptor (TCR) alphabeta(+) TCC were generated to investigate the nature of the drug-T cell interaction as well as the cross-reactivity with other quinolones. The use of eight different quinolones as antigens (Ag) revealed three patterns of cross-reactivity: clones exclusively reacting with the eliciting drug, clones with a limited cross-reactivity and clones showing a broad cross-reactivity. The TCC recognized quinolones directly without need of processing and without covalent association with the major histocompatability complex (MHC)-peptide complex, as glutaraldehyde-fixed Ag-presenting cells (APC) could present the drug and washing quinolone-pulsed APC removed the drug, abrogating the reactivity of quinolone-specific TCC. CONCLUSION: Our data show that T cells are involved in delayed immune reactions to quinolones and that cross-reactivity among the different quinolones is frequent.

Electrochemiluminescence of terbium (III)-two fluoroquinolones-sodium sulfite system in aqueous solution.

The electrochemiluminescence (ECL) of Tb3+-enoxacin-Na2SO3 system (ENX system) and Tb3+-ofloxacin-Na2SO3 system (OFLX system) in aqueous solution is reported. ECL is generated by the oxidation of Na2SO3, which is enhanced by Tb3+-fluoroquinolone (FQ) complex. The ECL intensity peak versus potential corresponds to oxidation of Na2SO3, and the ECL emission spectra (the peaks are at 490, 545, 585 and 620 nm) match the characteristic emission spectrum of Tb3+, indicating that the emission is from the excited state of Tb3+. The mechanism of ECL is proposed and the difference of ECL intensity between ENX system and OFLX system is explained. Conditions for ECL emission were optimized. The linear range of ECL intensity versus concentrations of pharmaceuticals is 2.0 x 10(-10) -8.0 x 10(-7)mol l(-1) for ENX and 6.0 x 10(-10) -6.0 x 10(-7)mol l(-1) for OFLX, respectively. A theoretical limit of detection is 5.4 x 10(-11)mol l(-1) for ENX and 1.6 x 10(-10)mol l(-1) for OFLX, respectively. The ECL was satisfactorily applied to the determination of the two FQs in dosage form and urine sample.