RESUMEN
New inhibitors of the bacterial transferase MraY are described. Their structure is based on an aminoribosyl-O-uridine like scaffold, readily obtained in two key steps. The amino group can be coupled with proline or guanylated. Alternatively, these amino, prolinyl or guanidinyl groups can be introduced through a triazole linker. Biological evaluation of these compounds on MraY from Bacillus subtilis revealed interesting inhibitory activity for both amino compounds.
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Transferasas/antagonistas & inhibidores , Antibacterianos/química , Antibacterianos/farmacología , Bacillus subtilis/enzimología , Proteínas Bacterianas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Transferasas/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos) , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
A library of bisphosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromophoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bisphosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bisphosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal.
Asunto(s)
Quelantes/síntesis química , Quelantes/farmacología , Difosfonatos/síntesis química , Difosfonatos/farmacología , Uranio/química , Uranio/farmacocinética , Animales , Sitios de Unión , Huesos/efectos de los fármacos , Huesos/metabolismo , Quelantes/química , Difosfonatos/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Estereoisomerismo , Distribución Tisular/efectos de los fármacos , Uranio/orinaRESUMEN
A simple and efficient method for constructing sulfur heterocycles was developed using a phosphine-catalyzed tandem umpolung addition and intramolecular cyclization of bifunctional sulfur pronucleophiles on arylpropiolates. The reaction offers a promising route to synthetically useful as well as biologically active heterocycles under neutral conditions.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Fosfinas/química , Compuestos de Azufre/síntesis química , Catálisis , Ciclización , Compuestos Heterocíclicos/química , Estructura Molecular , Rodaminas/química , Compuestos de Azufre/químicaRESUMEN
n-Tributylphosphine was found to efficiently catalyze the alpha-P addition of H-phosphonates, H-phosphinates, and H-phosphine oxide pronucleophiles on alkynes bearing phosphane oxide activating moieties. The reaction leads to 2-aryl-1-vinyl-1,1-diphosphane dioxide derivatives in good yields affording a new route to P-C-P backbones. The products of this reaction are easily converted to biologically important 1,1-bis-phosphonates analogues.