RESUMO
Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate.
Assuntos
Antibacterianos/síntese química , Furanos/síntese química , Oxazóis/síntese química , Oxazolidinonas/síntese química , Animais , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Furanos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos , Camundongos , Testes de Sensibilidade Microbiana , Oxazóis/farmacologia , Oxazolidinonas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.