RESUMO
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Metionina tRNA Ligase/antagonistas & inibidores , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Quinolonas , Staphylococcus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
Assuntos
Anti-Infecciosos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Metionina tRNA Ligase/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana , Enterococcus/efeitos dos fármacos , Enterococcus/enzimologia , Bactérias Gram-Positivas/enzimologia , Concentração Inibidora 50 , Staphylococcus/efeitos dos fármacos , Staphylococcus/enzimologia , Relação Estrutura-AtividadeRESUMO
Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.