RESUMEN
The essential oil of Rhododendron anthopogon was investigated by GC-MS, and seventeen compounds (representing approximately 98% of the oil) were identified. The major components of the aerial parts of the oil were the monoterpenes alpha-pinene, beta-pinene, limonene and the sesquiterpene delta-cadinene. Biological studies revealed a weak topical anti-inflammatory activity; a significant killing effect against some Gram-positive reference strains: Staphylococcus aureus, Enterococcusfecalis, Bacillus subtilis was measured; Mycobacterium tuberculosis reference strain and a clinical isolate of Candida, C. pseudotropicalis were killed by as low as 0.04% (v/v) essential oil. Moreover, the oil was able to reduce cancer cell growth independently of the cell line and the treatment protocols used.
Asunto(s)
Antibacterianos/química , Antifúngicos/química , Antituberculosos/química , Aceites Volátiles/química , Rhododendron/química , Animales , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Antituberculosos/aislamiento & purificación , Antituberculosos/farmacología , Bacterias/efectos de los fármacos , Candida/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Humanos , Ratones , Ratones Endogámicos , Mycobacterium tuberculosis/efectos de los fármacos , Aceites Volátiles/aislamiento & purificación , Aceites Volátiles/farmacologíaRESUMEN
2-Aryl-3-(1H-imidazol-1-yl and 1H-1,2,4-triazol-1-yl)-1H-indole derivatives were synthesized and tested for their in-vitro antifungal and antimycobacterial activities. These indole derivatives were devoid of antifungal activity against the tested strains of Candida spp. Yet, they exhibited an interesting antitubercular activity against Mycobacterium tuberculosis reference strain H(37)Rv.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Candida/efectos de los fármacos , Química Farmacéutica/métodos , Indoles/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Antibacterianos/farmacología , Antifúngicos/farmacología , Indoles/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H(37)Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Proteínas Bacterianas/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Oxadiazoles/química , Oxadiazoles/farmacología , Antituberculosos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Simulación por Computador , Inhibidores Enzimáticos del Citocromo P-450 , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/fisiología , Oxadiazoles/síntesis química , Unión Proteica , Esterol 14-Desmetilasa , Termodinámica , Tuberculosis/tratamiento farmacológicoRESUMEN
1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Pirazoles/química , Antibacterianos/química , Antifúngicos/química , Candida albicans/efectos de los fármacos , Hidrógeno/química , Imidazoles/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Monogalactosyl diglycerides with medium to long fatty acid acyl chains, were prepared and examined for antimicrobial activity against Gram positive, Gram negative bacteria and fungi. The study of their in vitro antimicrobial activity confirms the significant activity of some monogalactosyl diacylglycerol analogues and establishes for the galactose series that the 1,2-disubstitution and the octanoyl chain are the proper structural features for the maximum activity.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Diglicéridos/síntesis química , Diglicéridos/farmacología , Antiinfecciosos/química , Bacterias/efectos de los fármacos , Diglicéridos/química , Hongos/efectos de los fármacos , Espectrometría de Masas , Pruebas de Sensibilidad MicrobianaRESUMEN
From the fungus Stereum hirsutum have been isolated and identified two new epidioxysterols 1, 4, together with two known ones 2 and 3. Their structures were elucidated on the basis of spectroscopic analysis and chemical reactions. Epidioxysterols 1-4 have been shown to possess a significant activity against Mycobacterium tuberculosis.
Asunto(s)
Basidiomycota/química , Ésteres del Colesterol/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Antituberculosos/farmacología , Ésteres del Colesterol/química , Ésteres del Colesterol/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
New bis-imidazole derivatives have been synthesized and their antifungal and antimycobacterial activity was determined. Almost all compounds exhibited a moderate to good activity against two clinical isolates of Candida albicans 3038 and Candida glabrata 123. The same compounds showed an interesting killing activity against Mycobacterium tuberculosis H(37)Rv reference strain. Docking procedures combined with molecular dynamics simulations in the MM/PBSA framework of theory were applied to predict the binding mode of all compounds in the binding pocket of the cytochrome P450 14alpha-sterol demethylase (14DM) of C. albicans, for which no ligand-protein crystal structure is currently available. The results obtained in silico showed that the active compounds may interact at the active site of protein, and that their binding free energy values are in agreement with the corresponding experimental activity values.
Asunto(s)
Antifúngicos/farmacología , Antituberculosos/farmacología , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Imidazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Antifúngicos/síntesis química , Antifúngicos/química , Antituberculosos/síntesis química , Antituberculosos/química , Sitios de Unión , Unión Competitiva , Candida albicans/enzimología , Candida glabrata/enzimología , Simulación por Computador , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Imidazoles/síntesis química , Imidazoles/química , Ligandos , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Valor Predictivo de las Pruebas , Estructura Terciaria de ProteínaRESUMEN
Monoglucosyl and monogalactosyl diglycerides (MGDGs) with medium-long length acyl chains, identified as active components in Euphorbiaceae, were synthesized. They were examined for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. MGDGs with two octanoyl groups at both 1- and 2-positions showed the most potent activity. The stereoselectivity of pancreatic lipase was investigated in vitro where the preference for the 1 position in MGDGs is strictly related to the length of the acyl chains.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Química Farmacéutica/métodos , Diglicéridos/química , Lipasa/química , Páncreas/enzimología , Animales , Antiinfecciosos/química , Antifúngicos/química , Diseño de Fármacos , Ácidos Grasos/química , Hidrólisis , Modelos Químicos , Conformación Molecular , Mucor/metabolismo , Pseudomonas/metabolismo , TemperaturaRESUMEN
Monoglucosyl diglycerides with medium-long length fatty acid acyl chains were prepared and examined for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. The study of their in vitro antimicrobial activity confirms the significant activity of some monoglucosyl diacylglycerol analogues and establishes for the glucose series that the 1,2-disubstitution and the octanoyl chain are the proper structural features for the maximum activity.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Glucolípidos/síntesis química , Glucolípidos/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
OBJECTIVES: To synthesize new antimycobacterial and antifungal drugs that act by binding to sterol 14alpha-demethylase (14DM) and to characterize the drug-target protein interactions using computer-based molecular simulations. METHODS: Different series of imidazole and triazole derivatives having an azomethine linkage to pyridine 2-carboxamidrazone were designed and synthesized. Molecular dynamic simulations of the sterol 14DM (a mixed-function oxidase involved in sterol synthesis in eukaryotic and prokaryotic organisms) complexed with new azole derivatives have been performed to both qualify and quantify the protein-ligand interactions. MICs of the compounds were evaluated by reference assay and by the recently developed Microdilution Resazurin Assay (MRA). RESULTS: Halogenated derivatives showed good activity, with an MIC90 of 1 mg/L against 33 Candida spp. clinical strains; most compounds also had inhibitory activity against Mycobacterium tuberculosis reference and clinical strains, with MICs in the range 4-64 mg/L. Molecular modelling investigations showed that the active new compounds may interact at the active site of both the fungal and the mycobacterial cytochrome P450-dependent sterol-14alpha-demethylase and that the calculated binding free energy values are in agreement with the corresponding MIC values. CONCLUSIONS: The combined experimental and computational approach can be helpful in targeted drug design, thus yielding valuable information for the synthesis and prediction of activity of a second generation of inhibitors.
Asunto(s)
Antifúngicos/farmacología , Antituberculosos/farmacología , Imidazoles/farmacología , Triazoles/farmacología , Antifúngicos/química , Antituberculosos/química , Candida/efectos de los fármacos , Simulación por Computador , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Triazoles/químicaRESUMEN
3H-1,3,4-Oxadiazole-2-thione and 3H-1,3,4-oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H(37)Rv, whereas the corresponding thione derivatives were devoid of activity. Molecular modeling investigations showed that the active compounds may interact at the active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway and that their binding free energy values are in agreement with their MIC values.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Estructura MolecularRESUMEN
The less polar fraction of the methanolic extract from the plant Euphorbia peplis L. exhibited interesting antifungal and antitubercular activity. A complex mixture of four glucocerebrosides was responsible for this activity. Two new cerebrosides were isolated for the first time from Euphorbiaceae, 4 was assigned as 1-O-(beta-D-glucopyranosyl)-(2S,3S,4E,8E)-2N-[(2'R)-2'-hydroxy-hexadecanoyl]-4 (E), 8 (E)-octadecadiene-1,3-diol and 3 as the 1-O-(beta-D-glucopyranosyl)-(2S,3S,4R,8Z)-2N-[(2'R)-2'-hydroxytetracosanoyl]-8 (Z)-octadecene-1,3,4-triol. The structures were determined on the basis of chemical and spectroscopic evidences. Mass spectrometry of dimethyl disulfide derivatives was useful for the determination of the double-bond positions in the long-chain bases.
Asunto(s)
Antiinfecciosos/farmacología , Cerebrósidos/farmacología , Euphorbia/química , Antibacterianos/farmacología , Antiinfecciosos/aislamiento & purificación , Antifúngicos/farmacología , Antituberculosos/farmacología , Bacterias/efectos de los fármacos , Cerebrósidos/síntesis química , Cerebrósidos/química , Cerebrósidos/aislamiento & purificación , Euphorbiaceae/química , Hongos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A new rapid microdilution method, employing the dye resazurin as an indicator of mycobacterial growth, was developed to evaluate drug susceptibility of Mycobacterium tuberculosis reference strain H37Rv and of 13 M. tuberculosis susceptible or multidrug-resistant clinical strains. Different growth conditions were evaluated. The MICs of isoniazid, rifampicin, streptomycin and ethambutol were determined by the Microdilution Resazurin Assay (MRA) and the results compared with those obtained by the agar proportion method; complete agreement was always obtained. MRA resulted in a rapid, reliable, simple and inexpensive coloured method suitable for testing the susceptibility of M. tuberculosis clinical strains to first-line drugs; its employment in evaluating new antibacterial molecules is also suggested.
Asunto(s)
Antituberculosos/farmacología , Indicadores y Reactivos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Oxazinas/metabolismo , Xantenos , Agar , Recuento de Colonia Microbiana , Medios de Cultivo , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Tuberculosis Pulmonar/microbiologíaRESUMEN
[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of Mycobacterium tuberculosis H(37)Rv and three clinical isolates of M. tuberculosis.
Asunto(s)
Antituberculosos/síntesis química , Hidrazinas/síntesis química , Tiazoles/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Hidrazinas/química , Hidrazinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
The antimycobacterial role of eosinophil peroxidase (EPO), one of the most abundant granule proteins in human eosinophils, was investigated. Our data indicate that purified EPO shows significant inhibitory activity towards Mycobacterium tuberculosis H37Rv. On a molar basis, this activity was similar to that exhibited by neutrophil myeloperoxidase (MPO) and was both dose and time dependent. In contrast to the activity of MPO, which requires H(2)O(2), EPO also exhibited anti-M. tuberculosis activity in the absence of exogenously added peroxide. Morphological evidence confirmed that the mechanism of action of EPO against mycobacteria differs from that of MPO. While MPO kills M. tuberculosis H37Rv exclusively in the presence of hydrogen peroxide, it does not induce morphological changes in the pathogen. In contrast, EPO-treated bacteria frequently had cell wall lesions and eventually underwent lysis, either in the presence or in the absence of H(2)O(2).