RESUMEN
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/química , Oxazoles/química , Receptores de Mineralocorticoides/metabolismo , Animales , Sitios de Unión , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Microsomas/metabolismo , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Simulación del Acoplamiento Molecular , Oxazoles/síntesis química , Oxazoles/farmacocinética , Estructura Terciaria de Proteína , Ratas , Receptores de Mineralocorticoides/química , Relación Estructura-ActividadRESUMEN
Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.
Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida albicans/genética , Evaluación Preclínica de Medicamentos/métodos , Polinucleotido Adenililtransferasa/antagonistas & inhibidores , Alelos , Secuencia de Aminoácidos , Animales , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/crecimiento & desarrollo , Aspergillus fumigatus/metabolismo , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Mezclas Complejas/farmacología , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacología , Farmacorresistencia Fúngica , Fermentación , Heterocigoto , Ratones , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutación , Poliadenilación/efectos de los fármacos , Polinucleotido Adenililtransferasa/genética , Polinucleotido Adenililtransferasa/metabolismo , ARN Mensajero/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Resultado del TratamientoRESUMEN
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.