RESUMO
Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.
Assuntos
Adenosina/química , Antibacterianos/síntese química , DNA Ligases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , NAD/química , Adenina/química , Administração Oral , Animais , Antibacterianos/química , Disponibilidade Biológica , Cromatografia Líquida/métodos , DNA Ligases/química , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Flúor/química , Concentração Inibidora 50 , Espectrometria de Massas/métodos , Modelos Químicos , RatosRESUMO
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.
