RESUMO
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
Conformationally restricted analogues of the central linker unit of bacterial methionyl tRNA synthetase (MRS) inhibitors have been prepared. The (1S,2R)-cyclopentylmethyl moiety was identified as the preferred cyclic linker, with significant diastereo- and enantioselectivity of activity. Combination of this linker with an optimal substituted aryl right-hand side has resulted in a compound with exceptionally good antibacterial activity against staphylococci and enterococci, including antibiotic resistant strains.