RESUMEN
Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , ADN Ligasas/antagonistas & inhibidores , NAD/metabolismo , Naftiridinas/farmacología , Pirimidinas/farmacología , Antibacterianos/síntesis química , Proteínas Bacterianas/química , ADN Ligasas/química , Haemophilus influenzae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Naftiridinas/síntesis química , Pirimidinas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.
Asunto(s)
Antibacterianos/química , ADN Ligasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Cristalografía por Rayos X , ADN Ligasas/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , NAD/metabolismo , Estructura Terciaria de Proteína , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
The first examples of palladium-catalyzed oxidative amination of unactivated alkyl olefins have been identified. To be successful, these reactions must be conducted under cocatalyst-free conditions that involve direct dioxygen-coupled turnover of the palladium catalyst. The oxidative amination products of norbornene and other cyclic alkenes implicate a cis-aminopalladation mechanism.