RESUMEN
BACKGROUND: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed. METHODOLOGY/PRINCIPAL FINDINGS: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect. CONCLUSIONS/SIGNIFICANCE: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.
Asunto(s)
Antimaláricos/análisis , Antimaláricos/farmacología , Hepacivirus/genética , Hepacivirus/fisiología , ARN Viral/metabolismo , Replicación Viral/efectos de los fármacos , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Genoma Viral/genética , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Interferón-alfa/farmacología , Ribavirina/farmacología , Factores de Tiempo , Vitamina E/farmacologíaRESUMEN
Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.
Asunto(s)
Antimaláricos/administración & dosificación , Hexanoles/administración & dosificación , Malaria Falciparum/tratamiento farmacológico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/administración & dosificación , Animales , Antimaláricos/síntesis química , Antimaláricos/uso terapéutico , Carbono/química , Carbono/metabolismo , Ácidos Carboxílicos/química , Evaluación Preclínica de Medicamentos , Compuestos Ferrosos/metabolismo , Radicales Libres/química , Radicales Libres/metabolismo , Hexanoles/síntesis química , Hexanoles/uso terapéutico , Humanos , Concentración 50 Inhibidora , Malaria/parasitología , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos ICR , Oxidación-Reducción , Peróxidos/química , Peróxidos/metabolismo , Plasmodium berghei/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrollo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
Toxoplasma gondii is the etiologic agent of toxoplasmosis. Although the combination of sulfadiazine and pyrimethamine is used as therapy for this disease, these drugs can have serious side effects and its use is limited in pregnancy. Therefore there is a need for new anti-T. gondii drugs in the clinic. Some systems for T. gondii drug screening have been described, but these have limitations and can be difficult. In order to solve these problems, we established a system to screen drugs in vitro that involved using cell viability methods to calculate drug selectivities, which are Trypan blue, [3-(4,5-dimethylthiazol-zyl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliuzolium, inner salt] (MTS) method and lactate dehydrogenase (LDH) assay. These assays were simple to establish and perform. The IC(50) values calculated from the morphological assay were not significantly different from the EC(50) values calculated using the other three methods. In particular, the results of the morphological assay showed a distinct association with the MTS assay (R=0.9841). These assays could be used for a wide range of applications in the screening of new drugs and may provide an alternative to the techniques currently used to screen for candidate anti-T. gondii compounds in vitro. In this study, we also tested many compounds and identified some that had a good anti-T. gondii effect in vitro based on the MTS assay. This simple and fast system allowed us to determine which compounds to investigate further using in vivo experiments.
Asunto(s)
Coccidiostáticos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Toxoplasma/efectos de los fármacos , Animales , Colorantes , Evaluación Preclínica de Medicamentos/normas , Ensayo de Inmunoadsorción Enzimática , Células HeLa , Humanos , Concentración 50 Inhibidora , L-Lactato Deshidrogenasa/análisis , Pirimetamina/farmacología , Espiramicina/farmacología , Sulfadiazina/farmacología , Toxoplasma/fisiología , Azul de TripanoRESUMEN
Several beta-carbolines including naturally occurring substances and their corresponding cationic derivatives were synthesized and evaluated for antimalarial (antiplasmodial) activity in vitro and in vivo. A tetracyclic carbolinium salt was elucidated for antileishmanial and antitrypanosomal activities in vitro as well as antiplasmodial activity. Quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral beta-carbolines and a good correlation was observed between pi-delocalized lipophilic cationic (DLC) structure and antimalarial efficacy. beta-Carbolinium compounds exhibit medium suppressive activity in vivo against rodent malaria.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/uso terapéutico , Carbolinas/síntesis química , Carbolinas/uso terapéutico , Animales , Antimaláricos/farmacología , Carbolinas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Malaria/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Plasmodium berghei/efectos de los fármacosRESUMEN
Aqueous extracts of 6 traditional Korean medicines used to treat malaria were tested in vitro for their antimalarial activity against Plasmodium falciparum. The EC50 values for the herbal extracts were in the range 1.4-8.1 microg/ml. Significant antimalarial activity was observed with Coptis japonica (EC50=1.4 microg/ml), but it demonstrated no selective toxicity (selectivity=1). In contrast, Kalopanax pictus showed antimalarial activity (EC50=4.6 microg/ml) and higher selective toxicity (>4). This indicated that K. pictus may be potent for a new antimalarial agent.
Asunto(s)
Antimaláricos/farmacología , Preparaciones de Plantas/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/aislamiento & purificación , Línea Celular Tumoral , Humanos , Corea (Geográfico) , Medicina Tradicional de Asia Oriental , Ratones , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Preparaciones de Plantas/aislamiento & purificación , Plasmodium falciparum/crecimiento & desarrolloRESUMEN
Among 42 extracts, prepared from 14 medicinal plants used in Vietnamese traditional medicine to treat malaria, 24 were found to have antiplasmodial activity by inhibiting the growth of the chloroquine-resistant Plasmodium falciparum strain FCR-3 with EC(50) values less than 10 microg/ml. Each medicinal plant possessed at least one active extract. The methanol extract of Coscinium fenestratum had the strongest antiplasmodial activity with EC(50) value of 0.5 microg/ml. Activity-guided fractionation led to identification of berberine as the major active constituent.