RESUMEN
A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.
Asunto(s)
Calcitonina/biosíntesis , Pirimidinas/síntesis química , Sulfonamidas/síntesis química , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Calcitonina/genética , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Genes Reporteros , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Radioinmunoensayo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Activación Transcripcional , Xantinas/química , Xantinas/farmacologíaRESUMEN
Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at Asunto(s)
Antibacterianos/síntesis química
, Proteínas Bacterianas/antagonistas & inhibidores
, Peptidoglicano/efectos de los fármacos
, Transferasas/antagonistas & inhibidores
, Antibacterianos/farmacología
, Pared Celular/enzimología
, Interacciones Hidrofóbicas e Hidrofílicas
, Nucleótidos
, Péptidos
, Peptidoglicano/análogos & derivados
, Peptidoglicano/biosíntesis
, Peptidoglicano/farmacología
, Staphylococcus epidermidis/enzimología
, Staphylococcus epidermidis/ultraestructura
, Relación Estructura-Actividad
, Transferasas (Grupos de Otros Fosfatos Sustitutos)
, Urea
RESUMEN
Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.
Asunto(s)
Antibacterianos/síntesis química , Pared Celular/metabolismo , Staphylococcus aureus/metabolismo , Antibacterianos/farmacología , Pared Celular/efectos de los fármacos , Farmacorresistencia Bacteriana , Genes Bacterianos/genética , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimologíaRESUMEN
Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.