RESUMO
Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.
Assuntos
Antituberculosos/farmacologia , Mefloquina/farmacologia , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Mefloquina/síntese química , Mefloquina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Isótopos de Fósforo , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-AtividadeRESUMO
Background and Introduction: Mefloquine, a drug used to prevent and treat malaria is described possessing activity against the Mycobacterium tuberculosis (Mtb) as well as against multidrugresistant tuberculosis (MDR) and other types of bacteria. Despite their importance, few compounds based on the Mefloquine nucleus have been synthesized and evaluated against TB. MATERIALS AND METHODS: For the synthesis of all the compounds based on the Mefloquine nucleus we used a synthetic route which utilized the key derivative 4-methoxy-2,8-bis(trifluoromethyl)quinoline 2 as starting material. The compounds 3 (a-c), 4 (a-b) were synthesized after one step by reaction of 2 with appropriate amines substituted. The chloro derivatives 5 and 6 were obtained from compounds 4b and 4a by treatment with SOCl2 in CH2Cl2 at reflux in 75 and 80% yield, respectively. The analogue 6 was converted to 7 after treatment with ethanolamine under heating at 90oC in 64% yield and to the azido derivative 8 in 56% after reaction with sodium azide in MeOH at reflux for 2 h. The analogue 9 was obtained after reaction of 5 with ethanolamine at 90oC for 1 h in 90% yield. All the new compounds were identified by detailed spectral data, including 1H NMR, 13C NMR and high resolution mass spectra. All the compound were evaluated for their in vitro antibacterial activity against sensitive Mycobacterium tuberculosis ATCC 27294, using the microplate Alamar Blue assay (MABA). The more active compounds 3c, 7, and 9 were also evaluated against resistant strain SR 2571/0215 (resistant to Rifampicin and Isoniazid) by above method. All compounds were tested against three cancer cell lines: SF-295 (glioblastoma), HCT-116 (colon) and PC-3 (prostate) using the MTT assay. RESULTS: All the planned ten compounds were synthetically obtained in good global yield, displaying activity against sensitive Mycobacterium tuberculosis in vitro, with exception of one, with MIC values between 37.2 and 154.8 µM. The compounds 3c (37.2 µM), 7 (68.1 µM) and 9 (65.6 µM) showed the highest activity in this series with MIC values similar when compare to the standard Mefloquine (30 - 60 µM), being 3c the most potent. The more active compounds 3c, 7, and 9 were also evaluated against resistant strain, displaying MIC of 37.2, 136.2 and 65.6 µM, respectively. All compounds were tested against three cancer cell lines and showed low cytotoxicity. CONCLUSION: All synthesized compounds, with the exception of 5, exhibited activity against the Mtb. Compound 3c was the most potent against resistant and sensitive Mtb in this series, with MIC value of 37.2 µM. All compounds showed low cytotoxicity. These findings could be considered a good model to develop possible lead compounds in the fight against TB based on Mefloquine nucleus.
Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Mefloquina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mefloquina/síntese química , Mefloquina/química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
The antiparasitic properties of antiparasitic drugs are believed to be associated with their interactions with the protozoan membrane, encouraging research on the identification of membrane sites capable of drug binding. In this study, we investigated the interaction of mefloquine hydrochloride, known to be effective against malaria, with cell membrane models represented by Langmuir monolayers of selected lipids. It is shown that even small amounts of the drug affect the surface pressure-area isotherms as well as surface vibrational spectra of some lipid monolayers, which points to a significant interaction. The effects on the latter depend on the electrical charge of the monolayer-forming molecules, with the drug activity being particularly distinctive for negatively charged lipids. Therefore, the lipid composition of the monolayer modulates the interaction with the lipophilic drug, which may have important implications in understanding how the drug acts on specific sites of the protozoan membrane.
Assuntos
Antimaláricos/química , Membrana Celular/química , Mefloquina/química , Membranas Artificiais , Lipossomas Unilamelares/químicaRESUMO
A series of 23 racemic mefloquine-oxazolidine derivatives, 4-[3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines, derived from (R*, S*)-(±)-mefloquine and arenealdehydes, have been evaluated for their activity against four cancer cell lines (HCT-8, OVCAR-8, HL-60, and SF-295). Good cytotoxicities have been determined with IC50 values ranging from 0.59 to 4.79 µg/mL. In general compounds with aryl groups having strong electron-releasing substituents, such as HO and MeO, or electron-rich heteroaryl groups, for example imidazol-2-y-l, are active. However, other factors such as steric effects may play a role. As both the active and non-active conformations of the mefloquine-oxazolidine derivatives are similar, it is concluded that molecular conformations do not play a significant role either. This study is the first to evaluate mefloquine derivatives as antitumor agents. The mefloquine-oxazolidine derivatives are considered to be useful leads for the rational design of new antitumor agents.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Mefloquina/química , Oxazóis/química , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Quinolinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33µM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1µM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.
Assuntos
Aldeídos/química , Antituberculosos/química , Antituberculosos/farmacologia , Etambutol/farmacologia , Mefloquina/química , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazóis/química , Animais , Antituberculosos/síntese química , Células Cultivadas , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Etambutol/química , Mefloquina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Mycobacterium tuberculosis/isolamento & purificação , Oxazóis/farmacologiaRESUMO
A simple HPLC method for determination of mefloquine hydrochloride in tablets was developed and validated. The separation was carried out on an Xterra RP18 (250 x 4.6 mm id, 5 pm particle size) analytical column. The mobile phase was 0.05 M monobasic potassium phosphate buffer (pH 3.5)-methanol (40 + 60, v/v). The flow rate and wavelength were set to 1 mL/min and 283 nm, respectively. The method was specific for mefloquine hydrochloride in the presence of hydrolytic, oxidative, and photolytic degradation products. It was also linear, precise, accurate, and robust, being suitable for routine QC analyses and stability studies. The developed HPLC method was compared to a previously described spectrophotometric method.
Assuntos
Antimaláricos/química , Cromatografia Líquida de Alta Pressão/métodos , Mefloquina/química , Estrutura Molecular , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Comprimidos/químicaRESUMO
In this work, we report the synthesis and the antitubercular evaluation of 16 new mefloquine derivatives, formed from reactions between mefloquine and benzaldehydes, with the activity expressed as the minimum inhibitory concentration (MIC) in µM. The compounds were non-cytotoxic and exhibited an important activity (12.6 µM). The appreciable activity of these compounds can be considered an important finding for the rational design of new leads for anti-TB compounds.
Assuntos
Antituberculosos/farmacologia , Mefloquina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Cristalografia por Raios X , Desenho de Fármacos , Mefloquina/síntese química , Mefloquina/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Relação Estrutura-AtividadeRESUMO
The crystal structure of a monohydrate of (+/-)-mefloquinium chloride, (+/-)-[MEFHCl.(H(2)O)], has been obtained from data collected at 120 K. Further details of the crystal structure of a hemihydrate, (+/-)-[MEFHCl*(1/2)(H(2)O)], previously determined at room temperature, are also reported from data collected at 120 K. The structural data, along with X-ray powder patterns, infrared spectra (both mid and near IR ranges) and DSC data, provide definitive evidence for the two hydrates. Further attempts to completely resolve the crystal structure of a tetragonal solvated phase failed due to the considerable disorder, involving the solvates, either water or methanol, even at 120 K, however X-ray powder pattern and infrared spectral and DSC data for this phase are also reported. Comparisons of the data obtained for the hydrates in this study, with X-ray powder patterns and mid-infrared spectra of previously reported forms of (+/-)-mefloquinium chloride have highlighted erroneous assignments and allowed structural identification of previously and differently designated forms.
Assuntos
Coleta de Dados/métodos , Mefloquina/química , Solventes/química , Temperatura , Cristalização , Difração de Raios X/métodosRESUMO
A method for the simultaneous analysis of the enantiomers of mefloquine (MQ) and its main metabolite carboxymefloquine (CMQ) in plasma is described for the first time. The assay involves two-step liquid-phase microextraction (LPME) and enantioselective high-performance liquid chromatography. In the first LPME step, the enantiomers of MQ were extracted from an alkalinized sample through a thin layer of di-n-hexyl ether immobilized in the pores of the hollow fiber and into 0.01 M perchloric acid as acceptor solution. In the second LPME step, the same sample was acidified to enable the extraction of CMQ using the same organic solvent and 0.05 M sodium hydroxide as acceptor phase. The analytes were resolved on a Chirobiotic T column in the polar-organic mode of elution and detected at 285 nm. The recovery rates from 1 mL of plasma were in the range 35-38%. The method presented limits of quantification of 50 ng/mL for all analytes and was linear up to 1,500 and 3,000 ng/mL for the enantiomers of MQ and CMQ, respectively. The plasmatic concentrations of (+)-(RS)-MQ were higher than those of (-)-(SR)-MQ after oral administration of the racemic drug to rats.
Assuntos
Fracionamento Químico/métodos , Cromatografia Líquida de Alta Pressão/métodos , Mefloquina/análogos & derivados , Mefloquina/sangue , Mefloquina/metabolismo , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Mefloquina/química , Estrutura Molecular , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo , Fatores de TempoRESUMO
A simple and rapid method, which involves liquid-phase microextraction (LPME) followed by HPLC analysis using Chiralpak AD column and UV detection, was developed for the enantioselective determination of mefloquine in plasma samples. Several factors that influence the efficiency of three-phase LPME were investigated and optimized. Under the optimal extraction conditions, the mean recoveries were 33.2 and 35.0% for (-)-(SR-)-mefloquine and (+)-(RS)-mefloquine, respectively. The method was linear over 50-1500 ng/ml range. Within-day and between-day assay precision and accuracy were below 15% for both enantiomers at concentrations of 150, 600 and 1200 ng/ml. Furthermore, no racemization or degradation were seen with the method described.