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1.
Artigo em Inglês | MEDLINE | ID: mdl-31931327

RESUMO

Acute bacterial skin and skin structure infections are one of the most frequent infectious disease requiring hospitalization for treatment. Delafloxacin is a clinically approved fluoroquinolone antibiotic for the treatment of ABSSSIs. In spite of being marketed since 2017, there is no published analytical method for quantification of delafloxacin in biological samples. Herein, a selective and sensitive UPLC-MS/MS method was developed and validated for quantitative analysis of delafloxacin in rat plasma and rabbit aqueous humour samples. The liquid liquid extraction (using ethyl acetate) was used for analyte extraction form rat plasma, whereas protein precipitation (acetonitrile) was used for aqueous humour samples preparations. An Acquity UPLC BEH C18 column was used for chromatographic separation of delafloxacin and internal standard (rivaroxaban). The mobile phase composition of acetonitrile (containing 0.1% formic acid) and 10 mM ammonium acetate in ratio of 60:40 were used for sample elution at 300 µL/min flow rate. The electrospray ionization operated in positive mode was used for sample ionization and detection of analyte and internal standard were performed by multiple reaction monitoring (MRM) mode. The MRM transitions were set to 441.14 > 379.09 and 436.89 > 144.87 for delafloxacin and internal standard, respectively. The method was validated as per USFDA guideline for bioanalytical method and all the evaluated parameters were within the acceptable ranges. The developed method in plasma was successfully used to analyze samples in pharmacokinetic study of newly developed stearic acid-chitosan solid lipid nanoparticles formulation of delafloxacin in rat.


Assuntos
Humor Aquoso/química , Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas/análise , Espectrometria de Massas em Tandem/métodos , Animais , Fluoroquinolonas/sangue , Fluoroquinolonas/química , Modelos Lineares , Masculino , Coelhos , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
2.
J Chromatogr Sci ; 57(10): 867-873, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31602483

RESUMO

Nadifloxacin, mometasone furoate and miconazole nitrate are formulated together as a topical antifungal dosage form. In this work, a reversed-phase ultra-performance liquid chromatographic method coupled with a diode array detector (RP-UPLC-DAD) was developed and validated to determine nadifloxacin, mometasone furoate and miconazole nitrate simultaneously in their bulk powder, in pharmaceutical preparation and in spiked human plasma samples. Separation was achieved on an ACQUITY UPLC C18 column of 2.2 µm particle size (2.1 × 100 mm) via isocratic elution using a mobile phase consisting of methanol, acetonitrile and water with ratio (50:20:30; v/v/v) and 0.1 g ammonium acetate, then pH was adjusted to (7.00) using acetic acid, flow rate 0.6 mL/min, temperature 30°C and UV detection at 220 nm. The method is linear in a range from 5 to 400 µg/mL for both nadifloxacin and miconazole nitrate and from 20 to 500 µg/mL for mometasone furoate. The method was validated according to the ICH guidelines then applied successfully to determine the mentioned drugs in their pharmaceutical preparation and spiked human plasma samples. For plasma samples, the results showed that the method can determine nadifloxacin, mometasone furoate and miconazole nitrate in human plasma samples with high accuracy and precision.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas/análise , Miconazol/análise , Furoato de Mometasona/análise , Quinolizinas/análise , Cromatografia de Fase Reversa , Fluoroquinolonas/sangue , Fluoroquinolonas/química , Humanos , Limite de Detecção , Modelos Lineares , Miconazol/sangue , Miconazol/química , Furoato de Mometasona/sangue , Furoato de Mometasona/química , Quinolizinas/sangue , Quinolizinas/química , Reprodutibilidade dos Testes
3.
Chemosphere ; 239: 124737, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493755

RESUMO

Antibiotics are of concern due to their prevalent detection in aquatic environment. Sulfate radical based advanced oxidation processes show a great capacity to degrade antibiotics, but the mechanisms are still unclear. In this work, the degradation mechanism of fluoroquinolones (FQs), a major group of antibiotics, in UV/Fe2+/PMS was deeply investigated. The degradation process was in-situ and real-time monitoring by illumination-assisted droplet spray ionization mass spectrometry. A series of reactive intermediates were captured, and further characterized by high-resolution mass spectrometry (HRMS) and tandem MS. About 50 different transformation products have been identified for ciprofloxacin and norfloxacin. More than 15 products were the first time reported. Taking into consideration of the sequential formation and intensity change of intermediates, the feasible and complete transformation pathways of FQs were proposed. Compared with the photolysis process, the defluorination of FQs was not observed in this system. This work provided abundant information of FQs degradation by persulfate advanced oxidation processes (AOPs) and meanwhile demonstrated the importance of HRMS and on-line MS in mechanism research of AOPs.


Assuntos
Antibacterianos/química , Fluoroquinolonas/química , Peróxidos/química , Sulfatos/química , Ciprofloxacino/química , Ferro/química , Espectrometria de Massas , Norfloxacino/química , Oxirredução , Fotólise , Ácidos Sulfúricos/química , Raios Ultravioleta , Poluentes Químicos da Água/química
4.
Comput Biol Chem ; 84: 107167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31855781

RESUMO

BACKGROUND: Hepatitis C Virus (HCV) infection is a major public health concern across the globe. At present, direct-acting antivirals are the treatment of choice. However, the long-term effect of this therapy has yet to be ascertained. Previously, fluoroquinolones have been reported to inhibit HCV replication by targeting NS3 protein. Therefore, it is logical to hypothesize that the natural analogs of fluoroquinolones will exhibit NS3 inhibitory activity with substantially lesser side effects. METHOD: In this study, we tested the application of a recently devised integrated in-silico Cheminformatics-Molecular Docking approach to identify physicochemically similar natural analogs of fluoroquinolones from the available databases (Ambinter, Analyticon, Indofines, Specs, and TimTec). Molecular docking and ROC curve analyses were performed, using PatchDock and Graphpad software, respectively, to compare and analyze drug-protein interactions between active natural analogs, Fluoroquinolones, and HCV NS3 protein. RESULT: In our analysis, we were able to shortlist 18 active natural analogs, out of 10,399, that shared physicochemical properties with the template drugs (fluoroquinolones). These analogs showed comparable binding efficacy with fluoroquinolones in targeting 32 amino acids in the HCV NS3 active site that are crucial for NS3 activity. Our approach had around 80 % sensitivity and 70 % specificity in identifying physicochemically similar analogs of fluoroquinolones. CONCLUSION: Our current data suggest that our approach can be efficiently applied to identify putative HCV drug inhibitors that can be taken for in vitro testing. This approach can be applied to discover physicochemically similar analogs of virtually any drug, thus providing a speedy and inexpensive approach to complement drug discovery and design, which can tremendously economize on time and money spent on the screening of putative drugs.


Assuntos
Antivirais/metabolismo , Descoberta de Drogas/métodos , Inibidores Enzimáticos/metabolismo , Fluoroquinolonas/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Domínio Catalítico , Inibidores Enzimáticos/química , Fluoroquinolonas/química , Hepacivirus/enzimologia , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
5.
Sci Total Environ ; 688: 1205-1215, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31726551

RESUMO

As antibiotics are widely consumed, fluoroquinolones (FQs) behave to have huge hidden danger to human health. Various agricultural residues have potential to produce biochar rich in porous structure for adsorption of contaminants. In this study, potato leaves and stems were pyrolyzed at 500 °C under anoxic condition for biochar (BC) preparation. At the same conditions, magnetic biochar (MBC) and humic acid (HA) coated magnetic biochar (HAB) were also prepared. In particular, characterizations of HAB showed the extensive coating of HA on MBC surface and introducing more oxygen-containing groups, which may promote the adsorption capacity of biochar. Three typical FQs (ciprofloxacin (CIP), norfloxacin (NOR) and enrofloxacin (ENR)) were used as target contaminants to further investigate the adsorption property of HAB. Compared with BC and MBC, novel adsorbent HAB due to introduction of HA exhibited better FQs adsorption ability, and its maximum adsorption capacity for CIP, NOR and ENR were 1.80, 1.67 and 1.70 times higher than those of MBC and were 3.40, 2.88, 2.96 times higher than those of raw BC, respectively. Pseudo-second-order kinetic model and Langmuir isotherm model could describe the process of FQs adsorbed on HAB more appropriately, and thermodynamic results illustrated that the sorption process was spontaneous and endothermic. In addition, FQs adsorption by HAB was increased with initial solution pH from 3.0 to 10.0, while it was slightly decreased with ionic strength rising (0.001-0.1 M CaCl2). Combined with FTIR results, high FQs removal efficiency could be attributed to electrostatic, hydrophobic, H-bond and π-π EDA interactions.


Assuntos
Carvão Vegetal/química , Fluoroquinolonas/química , Substâncias Húmicas/análise , Poluentes Químicos da Água/química , Purificação da Água/métodos , Antibacterianos
6.
Pak J Pharm Sci ; 32(3 Special): 1301-1306, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551207

RESUMO

It is known that resistance of bacteria is one of the major issues in drug treatment. To cope this issue, it is required to synthesize new analogues which contest against mutated bacteria. This research study included synthesis of several derivatives of moxifloxacin by adding different phenol and alkyl halide at third position of carboxylic group with esterification reaction and the structures of synthesized derivatives were characterized by spectroscopic techniques i.e. 1H NMR, FT-IR and mass-spectrometry. In continuation, antimicrobial activities of the analogues were also evaluated against number of Gram-positive, Gram-negative bacteria and fungi. The experimental results of novel derivatives exhibit significant antibacterial and antifungal profile in which so many synthesized derivatives influenced a similar and enhanced activity against selected microbes that were S. typhi, P. mirabilis, P. aeruginosa, S. flexneri, B. subtilis as compared to the moxifloxacin. Moreover, few innovative derivatives were also produced better anti-fungal activity against F. solani and T. rubrum. Furthermore, the enzymatic activity of all analogues has been analyzed against urease and carbonic anhydrase and concluded that C2 was selected inhibitor of urease enzyme.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Moxifloxacina/química , Antibacterianos/síntese química , Antifúngicos/síntese química , Avaliação Pré-Clínica de Medicamentos , Ésteres/química , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Artigo em Inglês | MEDLINE | ID: mdl-31470687

RESUMO

Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure-activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/química , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/química , Oxazinas/efeitos adversos , Oxazinas/química , Desenho de Drogas , Lógica Fuzzy , Humanos , Relação Quantitativa Estrutura-Atividade
8.
Chemosphere ; 237: 124484, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31394442

RESUMO

The degradation of flumequine (FLU) in aqueous solution by ultraviolet (UV)-activated peroxymonosulfate (PMS) was investigated in this work. Under the conditions of [PMS]0:[FLU]0 = 1:1, T = 25 ±â€¯2 °C, pH = 7.0 ±â€¯0.1, nearly complete removal of FLU was achieved after 60 min. The effects of various operating parameters, including oxidant doses, pH, the presence of typical ions (NH4+、Mg2+、Fe3+、Cl-、NO3-、HCO3-) and humic acid were evaluated. It was found that the pseudo-first-order rate constants of FLU degradation increased with increasing PMS dosage and decreasing solution pH. The presence of Mg2+ could accelerate FLU removal, while Fe3+, HCO3-, NO3- and HA inhibited the reaction. Moreover, the degradation of FLU in different water matrices were also explored, and the removal followed the order of Tap water > Ultrapure water > River water > Secondary clarifier effluent. According to the control and radical quenching experiment results, direct photolysis and reactive radicals (SO4- and HO) contributed mainly to FLU degradation in the UV/PMS system. Initial FLU molecule underwent reactions such as hydroxylation, hydroxyl substitution, demethylation, decarboxylation/decarbonylation and ring opening, leading to the formation of nineteen oxidation products. The effective degradation by UV/PMS suggests a feasible technology for treating FLU in waters and wastewaters.


Assuntos
Fluoroquinolonas/química , Peróxidos/química , Poluentes Químicos da Água/química , Substâncias Húmicas , Radical Hidroxila , Cinética , Modelos Químicos , Oxidantes , Oxirredução , Fotólise , Soluções , Raios Ultravioleta , Água , Poluentes Químicos da Água/análise , Purificação da Água/métodos
9.
AAPS PharmSciTech ; 20(7): 278, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396732

RESUMO

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


Assuntos
Fluoroquinolonas/química , beta-Ciclodextrinas/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liofilização/métodos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Pós , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X
10.
Asian Pac J Cancer Prev ; 20(8): 2503-2514, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450926

RESUMO

Paramount efforts by pharmaceutical industry to identify new targets for obesity-diabetes (Diabesity) pharmacological intervention have led to a number of agents developed and directed at DPP IV [dipeptidyl peptidase IV] enzyme inhibition thereby enhancing endogenous insulinotropic incretins. Besides antioxidative-antiinflammtory molecules that inhibit accumulation of advanced glycation end products (AGEs) can be good candidates for ameliorating diabetic complications. Fluoroquinolones (FQs) have been identified recently as potent inhibitors of pancreatic lipase (PL). The suggested association between obesity and colorectal cancer initiated the evaluation of antiproliferative activity of the new FQs and TFQs against a panel of obesity related colorectal cells (HT29, HCT116, SW620 CACO2 and SW480). The aim of the current study is to examine the potential of newly synthesized FQs and triazolofluoroquinolones (TFQs) derivatives as dual inhibitors for glycation and inflammation, DPP IV inhibitors, PL inhibitors for dual management of obesity and diabetes, as well as antiprolifertaive efficacy against colorectal cancer cell lines. Sulforodamine B (SRB) colorimetric assay revealed that some derivatives exhibited unselective cytotoxity against HT29, HCT116, SW620 CACO2 and SW480. The superior antiglycation activity of the reduced derivatives 4a and 4b over that of aminoguanidine with respective IC50 (µM) values of 3.05±0.33 and 8.51±3.21; none of the tested synthetic compounds could perform equally effectively to Diprotin A, a dose dependent inhibitor of DPP IV. Compounds 4a, 5a, 3b, 4b and 5b demonstrated anti-inflammatory IC50 values exceeding that of indomethacin. Compounds 3a and 4a showed IC50 lower than 10 µM as PL inhibitors. In conclusion, FQ and TFQ derivatives may unveil new antiobesity and anticancer agents in the future. Our research qualifies FQs and TFQs as promising candidates for the development of related α-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fluoroquinolonas/farmacologia , Glicosilação/efeitos dos fármacos , Pancrelipase/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Antineoplásicos/química , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores da Dipeptidil Peptidase IV/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fluoroquinolonas/química , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular
11.
Environ Sci Pollut Res Int ; 26(33): 34345-34356, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31428965

RESUMO

Fluoroquinolones (FQs) occur broadly in natural media due to its extensive use, and it has systematic effects on our ecosystem and human immunity. In this study, long-root Eichhornia crassipes was reclaimed as a multi-functional activated carbon (MFAC) to remove fluoroquinolones (FQs) from contaminated water. To get insight into the adsorption mechanism, multiple measurements, including FTIR and XPS analyses, were employed to investigate the adsorption processes of ciprofloxacin and norfloxacin as well as the experiments of effect of exogenous factors on adsorption performances. The results confirmed that the adsorption of FQs by MFAC was mainly attributed to the electrostatic interaction, hydrogen bond interaction, and electronic-donor-acceptor (EDA) interaction. In addition, the kinetics and thermodynamics experiments demonstrated that the MFAC possessed great adsorption performance for FQs. According to the Langmuir model, the saturated adsorption capacities exceeded 145.0 mg/g and 135.1 mg/g for CIP and NOR at 303.15 K, respectively. The column experiments were conducted to explore the application performance of MFAC on the advanced treatment of synthetic water at different flow rates and bed depths. The adsorption capacity of CIP on MFAC was estimated by the Thomas models and the bed-depth service time (BDST) models, reaching 127.56 mg/g and 11,999.52 mg/L, respectively. These results also provide a valid approach for the resource recycling of the redundant long-root Eichhornia crassipes plants. Graphical abstract.


Assuntos
Carvão Vegetal/química , Eichhornia/química , Fluoroquinolonas/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Adsorção , Anti-Infecciosos , Ciprofloxacino , Ecossistema , Fluoroquinolonas/análise , Humanos , Cinética , Norfloxacino , Reciclagem , Termodinâmica , Água , Poluentes Químicos da Água/análise
12.
Int J Biol Macromol ; 137: 732-740, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31279886

RESUMO

Aminotransferases are widely employed as biocatalysts for the asymmetric synthesis of biologically active pharmaceuticals. Transaminase BpTA from Bacillus pumilus W3 can accept a broad spectrum of sterically demanding substrates, but it does not process the key five-membered ring intermediate of sitafloxacin. In the present study, we rationally constructed numerous single-point mutants and six multi-point mutants by combining the structural characteristics of transaminase and its substrates. Biochemical characteristics of wild-type and mutant enzymes were initially analyzed, and mutants I215M, I215F, and Y32L displayed increased catalytic efficiency, K155A, I215V and T252A completely lost enzyme activity. Residues K155 and T252 had a particularly strong influence on catalytic activity. Four multi-point mutants (L212M/I215M, Y32L/S190A/L212M/I215M, Y32L/Y159F/T252A and Y32W/Y159F/I215M/T252A) possess potential for industrial production of the key five-membered ring intermediate of sitafloxacin. Furthermore, mutants Y32L/Y159F/T252A and Y32W/Y159F/I215M/T252A can catalyze conversion of (R)-α-phenethylamine, albeit at an extremely low rate (<8%). In summary, mutants L212M/I215M and Y32L/S190A/L212M/I215M are more suitable for industrial production of the antibiotic, sitafloxacin, via an enzymatic approach.


Assuntos
Bacillus pumilus/enzimologia , Fluoroquinolonas/química , Fluoroquinolonas/metabolismo , Mutagênese Sítio-Dirigida , Transaminases/genética , Transaminases/metabolismo , Bacillus pumilus/genética , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Modelos Moleculares , Mutação , Domínios Proteicos , Estereoisomerismo , Especificidade por Substrato , Transaminases/química
13.
Appl Microbiol Biotechnol ; 103(17): 6933-6948, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332486

RESUMO

Although internationally recognized as the "highest priority critically important antimicrobials," fluoroquinolones are extensively used in both human and veterinary medicine. Poor metabolism and recalcitrance of fluoroquinolones have led to their worldwide presence in municipal wastewaters as well as in manure and, consequently, in several environmental compartments. Being one of the most widely used fluoroquinolones in human medicine and, aside from that, the main metabolite of the veterinary drug enrofloxacin, ciprofloxacin is the most frequently detected fluoroquinolone in effluents of European wastewater treatment plants. Due to serious global concerns about the increasing emergence of bacterial (multi)resistances toward the highly efficient fluoroquinolones, special attention has been paid to their environmental degradation by various microorganisms. This review summarizes research on microbial transformation and degradation of fluoroquinolones with special emphasis on ciprofloxacin, presents an overview of the main ciprofloxacin biotransformation products, and takes a closer look at their biological relevance. Furthermore, own data, experiences, and publications gathered from our recent research in the field are acknowledged.


Assuntos
Antibacterianos/metabolismo , Ciprofloxacino/metabolismo , Poluentes Ambientais/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Biodegradação Ambiental , Biotransformação , Ciprofloxacino/química , Ciprofloxacino/farmacologia , Poluentes Ambientais/química , Poluentes Ambientais/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/metabolismo , Fluoroquinolonas/farmacologia
14.
Arch Pharm (Weinheim) ; 352(7): e1800376, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215674

RESUMO

Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anti-cancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Fluoroquinolonas/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bactérias/efeitos dos fármacos , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
15.
Luminescence ; 34(6): 595-601, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31074200

RESUMO

In this paper, the interactions of pepsin with fluoroquinolones, including norfloxacin (NFX) or ofloxacin (OFX), were investigated using fluorescence spectroscopy. The effects of NFX or OFX on pepsin showed that the molecular conformation of pepsin and the microenvironment of tryptophan residues were changed under mimicked physiological conditions. Static quenching was suggested as a factor. Quenching constants and binding constants were determined and thermodynamic parameters were calculated at three temperatures (25°C, 31°C and 37°C). Molecular interaction distances (binding distance r) were obtained. Binding was enthalpy driven and the process was spontaneous. Synchronous fluorescence, three-dimensional fluorescence spectroscopy and molecular simulation were used for analysis. Interactions were further tested using molecular modelling. Quenching and binding constants of NFX with pepsin were the highest when testing NFX/OFX/fleroxacin/gatifloxacin with pepsin combinations. NFX was the strongest quencher, and affinity of NFX for pepsin was higher than that of OFX/fleroxacin/gatifloxacin.


Assuntos
Antibacterianos/química , Fluoroquinolonas/química , Pepsina A/química , Fleroxacino/química , Fluorescência , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Norfloxacino/química , Ligação Proteica , Espectrometria de Fluorescência
16.
Molecules ; 24(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027311

RESUMO

To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/química , Oxazolidinonas/química , Antibacterianos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 172: 109-130, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959322

RESUMO

Fluoroquinolones substituted with N-1 biphenyl and napthyl groups were discovered to act as catalytically inhibitors of human topoisomerases I and II, and to possess anti-proliferative activity in vivo. Structural requirements for these novel quinolones to inhibit catalytic activity of human topoisomerase I have not been explored. In this work novel derivatives of the N-1 biphenyl fluoroquinolone were designed, synthesized and evaluated to understand structural requirements of the C-3 carboxylic acid, C-6 fluorine, C-7 aminomethylpyrrolidine, C-8 methoxy, and the N-1 biphenyl functional groups for hTopoI inhibition. Characterization of each analog for inhibition of hTopoI catalytic inhibition reveals critical insight into structural requirements of these novel quinolones for activity. Additionally, results of DNA binding and modeling studies suggest that N-1 biphenyl fluoroquinolones intercalate between the DNA base pairs with the N-1 biphenyl functional group, rather than the quinolone core, and that this mode of DNA intercalation contributes to inhibition of hTopoI by these novel structures. The results presented here support further development and evaluation of N-1 biphenyl fluoroquinolone analogs as a novel class of anti-cancer agents that act through catalytic inhibition of hTopoI.


Assuntos
Compostos de Bifenilo/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Fluoroquinolonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
18.
Clin Biochem ; 68: 50-54, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30991036

RESUMO

OBJECTIVES: Fluoroquinolone antibiotics are commonly used in the treatment of infections and have previously been confirmed to cross-react with previous generations of opiates immunoassays. In this work we evaluated the cross-reactivity of the three fluoroquinolones in use at our institution with a panel of 10 urine drug screens. DESIGN AND METHODS: Drug preparations of levofloxacin, ciprofloxacin, and moxifloxacin that were designed for intravenous delivery were added to drug-free urine at varying concentrations. Spiked urine samples were screened for illicit and therapeutic drugs on an Abbott Architect c16000 automated chemistry analyzer. Percent cross-reactivity was calculated. RESULTS: Levofloxacin displayed clinically relevant cross-reactivity with the Abbott MULTIGENT opiates and Thermo CEDIA® buprenorphine immunoassays but did not cross-react with the Abbott MULTIGENT oxycodone or methadone immunoassays. Moxifloxacin displayed clinically relevant cross-reactivity only with the Abbott MULTIGENT amphetamine/methamphetamine assay. Ciprofloxacin did not cross-react with any of the 10 immunoassays. CONCLUSIONS: This study demonstrates that levofloxacin cross-reacts with modern immunoassays for two related opioids (buprenorphine and morphine) and moxifloxacin cross-reacts with the amphetamine/methamphetamine assay. Urine concentrations of these fluoroquinolones that are consistent with therapeutic use produced results above commonly used-cutoffs for positivity. This underscores the necessity of confirmatory testing of presumptively positive urine drug screens.


Assuntos
Buprenorfina/química , Reações Cruzadas , Fluoroquinolonas/química , Imunoensaio/métodos , Alcaloides Opiáceos/química , Anfetamina/química , Analgésicos Opioides/química , Humanos , Levofloxacino/química , Detecção do Abuso de Substâncias
19.
Biomed Chromatogr ; 33(7): e4532, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30861568

RESUMO

WCK 771 is an l-arginine salt of levonadifloxacin (LND) being developed in intravenous dosage form and has recently completed a phase III trial in India. The pharmacokinetics of WCK 771, a novel anti-MRSA fluoroquinolone, were examined in mice, rats, rabbits, dogs, monkeys and humans after systemic administration during pre-clinical and clinical investigations. Urine and serum were evaluated for identification of metabolites. It was observed that LND mainly follows phase II biotransformation pathways. All of the species showed a different array of metabolites. In mice, rabbit and dog, the drug was mainly excreted in the form of O-glucuronide (M7) and acyl glucuronide (M8) conjugates, whereas in rat and human major metabolite was sulfate conjugate (M6). Monkeys exhibited equal distribution of sulfate (M6) and glucuronide conjugates (M7, M8). In addition to these three major phase II metabolites; five phase I oxidative metabolites (M1, M2, M3, M4 and M5) were identified using liquid chromatography tandem mass spectrometry. Out of these eight metabolites M2, M3, M5, M7 and M8 are reported for the first time.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/urina , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Haplorrinos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Coelhos , Ratos
20.
Int J Biol Macromol ; 131: 806-811, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904527

RESUMO

Here we propose a metal-chelate approach to removal of fluoroquinolones from aqueous solutions using their ability to bind strongly divalent and trivalent metal ions immobilized in a polymer matrix. Metal-affine sorbents for ciprofloxacin uptake have been fabricated via chelation of Cu(II), Al(III), and Fe(III) ions by supermacroporous cryogel of carboxyalkyl chitosan derivative (N-(2-carboxyethyl)chitosan, CEC) cross-linked with hexamethylene diisocyanate in aqeous medium. We have shown that virgin CEC cryogel adsorbed ciprofoxacin in a cationic form via electrostatic interactions at pH > pICEC, but the efficacy of recovery was below 50% and strongly pH-dependent. Modification of CEC cryogel with Cu(II) and Al(III) ions improved the ciprofloxacin (CIP) recovery by up to 98% in the pH range 7-10, the sorption capacity and affinity for CIP of metal-chelate sorbents increased with metal content and reached maximum values of 280 and 390 mg/g for Cu(II) and Al(III)-chelated cryogels, respectively. The metal-chelated CEC cryogels were efficient for ciprofloxacin removal from solutions with environmentally relevant concentration (50 µg/L) and were applicable as monolith sorbents under dynamic conditions.


Assuntos
Alumínio/química , Quelantes/química , Quitosana/análogos & derivados , Ciprofloxacino/química , Cobre/química , Criogéis/química , Adsorção , Quitosana/química , Fluoroquinolonas/química , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Estrutura Molecular , Poluentes Químicos da Água
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