RESUMO
We report herein the preparation and anti-staphylococcal activity of a series of novel 11-deoxy-11-hydroxyiminorifamycins. Many of the compounds synthesized exhibit potent activity against wild-type Staphylococcus aureus with MICs equivalent to, or better than, rifamycin reference agents. In addition, some of the compounds retain potent activity against an intermediate rifamycin-resistant strain of Staphylococcus aureus. For instance, compound 5k exhibits an MIC of 0.12 microg/mL against an intermediate rifamycin-resistant strain, while the rifamycin reference agents, rifampin and rifalazil, exhibit MICs of 16 microg/mL and 2 microg/mL, respectively, against the same strain.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Iminas/química , Oxigênio/química , Rifamicinas/síntese química , Rifamicinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Hidroxilação , Estrutura Molecular , Rifamicinas/química , Relação Estrutura-AtividadeRESUMO
A novel series of spirorifamycins was synthesized and their antibacterial activity evaluated both in vitro and in vivo. This new series of rifamycins shows excellent activity against Staphylococcus aureus that is equivalent to rifabutin. However, some compounds of the series exhibit lower MICs than rifabutin against rifampin-resistant strains of S. aureus. Further, compound 2e exhibits comparable efficacy in vivo in a murine model of S. aureus septicemia model following administration by either oral or parenteral dosing routes.
Assuntos
Rifabutina/síntese química , Rifabutina/farmacologia , Animais , Antibacterianos/síntese química , Vias de Administração de Medicamentos , Camundongos , Testes de Sensibilidade Microbiana , Rifamicinas/síntese química , Rifamicinas/farmacologia , Sepse/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.