RESUMEN
The emergence of old and new antibiotic resistance created in the last decades revealed a substantial medical need for new classes of antimicrobial agents. The antimicrobial activity of sulfa drugs is often enhanced by complexation with metal ions, which is in concordance with the well-known importance of metal ions in biological systems. Besides, sulfonamides and its derivatives constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic, antithyroid, antiviral and anticancer activities, among others. The purpose of this work has been the obtainment, characterization and determination of biological properties (antibacterial, antifungal, mutagenicity and phytotoxicity) of a new Co(III)-sulfathiazole complex: Costz, besides of its interaction with bovine serum albumin (BSA). The reaction between sodium sulfathiazole (Nastz) and cobalt(II) chloride in the presence of H2O2 leads to a brown solid, [CoIII(stz)2OH(H2O)3], (Costz). The structure of this compound has been examined by means of elemental analyses, FT-IR, 1H NMR, UV-Visible spectrometric methods and thermal studies. The Co(III) ion, which exhibits a distorted octahedral environment, could coordinate with the N thiazolic atom of sulfathiazolate. The complex quenched partially the native fluorescence of bovine serum albumin (BSA), suggesting a specific interaction with the protein. The Costz complex showed, in vitro, a moderate antifungal activity against Aspergillus fumigatus and A. flavus. As antibacterial, Costz displayed, in vitro, enhanced activity respective to the ligand against Pseudomonas aeruginosa. Costz did not show mutagenic properties with the Ames test. In the Allium cepa test the complex showed cytotoxic properties but not genotoxic ones. These results may be auspicious, however, further biological studies are needed to consider the complex Costz as a possible drug in the future.
Asunto(s)
Cobalto/química , Complejos de Coordinación/síntesis química , Sulfatiazoles/química , Allium/efectos de los fármacos , Allium/crecimiento & desarrollo , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Aspergillus flavus/efectos de los fármacos , Aspergillus fumigatus/efectos de los fármacos , Bovinos , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Peróxido de Hidrógeno/química , Pruebas de Sensibilidad Microbiana , Pruebas de Mutagenicidad , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/crecimiento & desarrollo , Unión Proteica , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , SulfatiazolRESUMEN
A new series of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines 6a-g and 7a-g were obtained with high regioselectivity from the reaction of triamino- or tetraaminopyrimidines 4 and 5 with α,ß-unsaturated carbonyl compounds 3a-g based on 2,4-dichlorothiazol-5-carbaldehyde 1. Twelve of the synthesized compounds were selected and tested by US National Cancer Institute (NCI) for their antitumor activity against 60 different human tumor cell lines. Compounds 7d and 7g showed important GI50 ranges of 1.28-2.98 µM and 0.35-2.78 µM respectively under in vitro assays. In addition, 6a-g and 7a-g were tested for antifungal properties against the clinical important fungi Candida albicans and Cryptococcus neoformans. Although these compounds showed moderate activities against C. albicans, the 2-amino derivatives 7a-g and mainly 7a and 7b, showed high activity against standardized and clinical isolates of C. neoformans with MIC50 = 7.8-31.2 µg/mL, MIC80 = 15.6-31.2 µg/mL and MIC100 = 15.6-62.5 µg/mL. In addition, since both compounds were fungicide rather than fungistatic these thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines appear as good candidates for further development not only as antifungal but also as antitumor drugs.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Azepinas/farmacología , Pirimidinas/farmacología , Tiazoles/química , Antifúngicos/química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Candida albicans/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Forty four extracts from nine Baccharis spp. from the Caulopterae section were tested in combination with terbinafine against Trichophyton rubrum with the HTSS assay at six different ratios with the aim of detecting those mixtures that produced a ≥50% statistically significant enhancement of growth inhibition. Since an enhanced effect of a combination respective of its components, does not necessarily indicate synergism, three-dimensional (3D) dose-response surfaces were constructed for each selected pair of extract/antifungal drug with the aid of CombiTool software. Ten extracts showed synergistic or additive combinations which constitutes a 22% hit rate of the extracts submitted to evaluation. Four flavonoids and three ent-clerodanes were detected in the active Baccharis extracts with HPLC/UV/ESI-MS methodology, all of which were tested in combination with terbinafine. Results showed that ent-clerodanes but not flavonoids showed synergistic or additive effects. Among them, bacchotricuneatin A followed by bacrispine showed synergistic effects while hawtriwaic acid showed additive effects.
Asunto(s)
Antifúngicos/farmacología , Baccharis/química , Ensayos Analíticos de Alto Rendimiento/métodos , Naftalenos/farmacología , Extractos Vegetales/farmacología , Trichophyton/efectos de los fármacos , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Argentina , Cromatografía Líquida de Alta Presión , Diterpenos de Tipo Clerodano/química , Diterpenos de Tipo Clerodano/aislamiento & purificación , Diterpenos de Tipo Clerodano/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Programas Informáticos , Espectrometría de Masa por Ionización de Electrospray , Terbinafina , Trichophyton/crecimiento & desarrolloRESUMEN
New hetaryl- and alkylidenerhodanine derivatives 3a-d, 3e, and 4a-d were prepared from heterocyclic aldehydes 1a-d or acetaldehyde 1e. The treatment of several rhodanine derivatives 3a-d and 3e with piperidine or morpholine in THF under reflux, afforded (Z)-5-(hetarylmethylidene)-2-(piperidin-1-yl)thiazol-4(5H)-ones and 2-morpholinothiazol-4(5H)-ones 5a-d, 6a-d, and (Z)-5-ethylidene-2-morpholinothiazol-4(5H)-one (5e), respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry. Several of these compounds were screened by the U.S. National Cancer Institute (NCI) to assess their antitumor activity against 60 different human tumor cell lines. Compound 3c showed high activity against HOP-92 (Non-Small Cell Lung Cancer), which was the most sensitive cell line, with GI50 = 0.62 µM and LC50 > 100 µM from the in vitro assays. In vitro antifungal activity of these compounds was also determined against 10 fungal strains. Compound 3e showed activity against all fungal strains tested, but showed high activity against Saccharomyces cerevisiae (MIC 3.9 µg/mL).
Asunto(s)
Antifúngicos , Antineoplásicos , Compuestos Heterocíclicos con 2 Anillos , Saccharomyces cerevisiae/crecimiento & desarrollo , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
The design, synthesis, in vitro evaluation, and conformational study of nitrosopyrimidine derivatives acting as antifungal agents are reported. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines have displayed a significant antifungal activity against human pathogenic strains. In this paper, we report a new group of nitrosopyrimidines acting as antifungal agents. Among them, compounds 2a, 2b and 15, the latter obtained from a molecular modeling study, exhibited antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. We have performed a conformational and electronic analysis on these compounds by using quantum mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) obtained from B3LYP/6-31G(d) calculations. Our experimental and theoretical results have led us to identify a topographical template which may provide a guide for the design of new nitrosopyrimidines with antifungal effects.
Asunto(s)
Antifúngicos/química , Compuestos Nitrosos/química , Pirimidinas/química , Antifúngicos/síntesis química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candida tropicalis/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Enlace de Hidrógeno , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Compuestos Nitrosos/síntesis química , Compuestos Nitrosos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Teoría Cuántica , Relación Estructura-ActividadRESUMEN
Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH(3) at C-2 or the presence of one or two NO(2) groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up to 250 µg mL-1. In contrast, a 22% of fungal membrane damage was observed at concentrations = 1 × MIC and 71% at 4× MIC, when 2 was tested in the Cellular Leakage assay. The comparison of log P and MICs for all compounds revealed that the antifungal activity of the eugenol analogues would not to be related to lipophilicity.
Asunto(s)
Candida albicans/efectos de los fármacos , Eugenol/análogos & derivados , Eugenol/farmacología , Acetilación , Arthrodermataceae/efectos de los fármacos , Candida albicans/aislamiento & purificación , Candidiasis/microbiología , Membrana Celular/efectos de los fármacos , Pared Celular/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Interacciones Farmacológicas , Ergosterol/farmacología , Eugenol/síntesis química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Safrol/análogos & derivados , Safrol/síntesis química , Safrol/farmacología , Relación Estructura-Actividad , Tiña/microbiología , Trichophyton/efectos de los fármacos , Trichophyton/aislamiento & purificaciónRESUMEN
The synthesis, in vitro evaluation, and conformational study of penetratin analogues acting as antifungal agents are reported. Different peptides structurally related with penetratin were evaluated. Analogues of penetratin rich in Arg, Lys and Trp amino acids were tested. In addition, HFRWRQIKIWFQNRRM[O]KWKK-NH(2), a synthetic 20 amino acid peptide was also evaluated. These penetratin analogues displayed antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. In contrast, Tat peptide, a well-known cell penetrating peptide, did not show a significant antifungal activity against fungus tested here. We also performed a conformational study by means experimental and theoretical approaches (CD spectroscopic measurements and MD simulations). The electronic structure analysis was carried out from Molecular Electrostatic Potentials (MEP) obtained by using RHF/6-31G ab initio calculations. Our experimental and theoretical results permitted us to identify a topographical template which may provide a guide for the design of new peptides with antifungal effects.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Proteínas Portadoras/química , Proteínas Portadoras/farmacología , Hongos/efectos de los fármacos , Secuencia de Aminoácidos , Péptidos de Penetración Celular , Dicroismo Circular , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Método de Montecarlo , Conformación Proteica , Electricidad EstáticaRESUMEN
Stem-bark extracts, fractions and the isolated constituent, ellagic acid of Lafoensia pacari St. Hil. (Lythraceae) were in vitro assayed for antifungal activity against a panel of yeasts, hialohyphomycetes as well as dermatophytes with the microbroth dilution method. The EtOH extract and its fractions and ellagic acid exhibited activity against Candida spp and Saccharomyces cerevisiae with MIC values between 250-1000 µg/mL, but they showed no action against filamentous fungi and dermatophytes (MIC>1000 µg/mL). Active extracts were evaluated in Neurospora crassa hyphal growth inhibition and sorbitol assays and then the effect of ergosterol on the MIC of ellagic acid was studied. The active extracts and its fractions and ellagic acid showed a blotchy zone around the paper disk and induced malformations of the hypha. Besides, MIC of the ellagic acid against the Saccharomyces cerevisiae was raised from 62 to 250 µg/mL in the presence of sorbitol 0.8 M, suggesting that the ellagic acid would probably exert its action on fungal cell wall. These results indicate that ellagic acid might be the main active antifungal compound of Lafoensia pacari and further suggest that the mode of antifungal action of these extracts and ellagic acid could be associated with the inhibition of fungal cell wall.
Os extratos, frações e ácido elágico, isolados da entrecasca de Lafoensia pacari A. St.-Hil., Lythraceae, foram testados in vitro para atividade antifúngica, frente a um painel de leveduras, hialo-hifomicetos e dermatófitos, utilizando o método de microdiluição. O extrato EtOH, frações e ácido elágico exibiram atividade contra Candida spp. e Saccharomyces cerevisiae com valores de CIM entre 250-1000 µg/mL, porιm não mostraram ação contra fungos filamentosos e dermatófitos (CIM>1000 µg/mL). Os extratos ativos foram avaliados nos ensaios de inibição do crescimento das hifas de Neurospora crassa, no teste do sorbitol, e pelo estudo do efeito do ergosterol na CIM do ácido elágico. Os extratos ativos, frações e ácido elágico mostraram zonas manchadas ao redor dos discos de papel e induziram malformações nas hifas. Além disso, a CIM do ácido elágico contra Saccharomyces cerevisiae passou de 62 para 250 µg/mL na presença do sorbitol 0,8 M, sugerindo que o ácido elágico provavelmente poderia exercer ação na parede celular fúngica. Esses resultados indicam que o ácido elágico pode ser o principal composto antifúngico de Lafoensia pacari, sugerindo que o modo de ação antifúngico desses extratos e ácido elágico poderia estar associado à inibição da parede celular fúngica.
RESUMEN
The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Micosis/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Antifúngicos/toxicidad , Candidiasis/tratamiento farmacológico , Criptococosis/tratamiento farmacológico , Modelos Moleculares , Péptidos/toxicidad , Poecilia , Pruebas de Toxicidad AgudaRESUMEN
The present work describes the synthesis and antifungal evaluation of new 5-arylidene-(Z)-2-dimethylamino-1,3-thiazol-4-ones 4a-f, obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC(100), MIC(80), and MIC(50) of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 microg/mL.
Asunto(s)
Antifúngicos/farmacología , Cryptococcus neoformans/efectos de los fármacos , Tiazoles/farmacología , Antifúngicos/síntesis química , Arthrodermataceae/efectos de los fármacos , Cryptococcus neoformans/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis químicaRESUMEN
The synthesis, in vitro evaluation, and conformational study of RQIKIWFQNRRMKWKK-NH(2) (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC strains Candida albicans and Cryptococcus neoformans as well as clinical isolates of C. neoformans. Among the compounds tested, penetratin along with the nonapeptide RKWRRKWKK-NH(2) and the tetrapeptide RQKK-NH(2) exhibited significant antifungal activities against the Cryptococcus species. A comprehensive conformational analysis on the peptides reported here using three different approaches, molecular mechanics, simulated annealing and molecular dynamics simulations, was carried out. The experimental and theoretical results allow us to identify a topographical template which may provide a guide for the design of new compounds with antifungal characteristics against C. neoformans.