RESUMO
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.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , DNA Ligases/antagonistas & inibidores , NAD/metabolismo , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Antibacterianos/síntese química , Proteínas de Bactérias/química , DNA Ligases/química , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftiridinas/síntese química , Pirimidinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/química , DNA Ligases/antagonistas & inibidores , Inibidores Enzimáticos/química , Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Sítios de Ligação , Cristalografia por Raios X , DNA Ligases/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , NAD/metabolismo , Estrutura Terciária de Proteína , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
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.