RESUMO
A novel series of oxazolidinones were synthesized in which the morpholine C-ring of linezolid was replaced with homomorpholine. In addition to investigating the effect of a homomorpholine C-ring on antibacterial activity, the effect of des-, mono-, di-, and tri-fluoro substitution on the phenyl B-ring was investigated as well. Various C-5 functional groups were also examined, including acetamides and triazoles and carboxamides.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Morfolinas/química , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Antibacterianos/química , Oxazolidinonas/química , Relação Estrutura-AtividadeRESUMO
Due to the emergence of resistance to known antibiotics to various organisms, for example, Staphylococcus, Streptococcus, Enterococci, and Pseudomonas there is a renewed interest in the discovery of new antibacterials. Oxazolidinones, totally synthetic class of novel antibacterials, possess activity against drug-resistant Gram-positive pathogens, especially MRSA. Linezolid, the first approved drug from this class, has shown a great promise in saving lives of many patients by acting against drug-resistant Gram-positive organisms. However, its use is somewhat limited because of its myelotoxicity when used long term (>21 days). Various research groups are active in this area either to improve myelotoxicity profile of linezolid or to expand the spectrum of activity of linezolid. In spite of active research in this area, the discovery of an oxazolidinone possessing improved myelotoxicity compared to linezolid, linezolid-like efficacy, and PK remains challenging.
Assuntos
Antibacterianos/química , Oxazolidinonas/química , Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Oxazolidinonas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacosRESUMO
A novel series of conformationally restricted oxazolidinones was synthesized, in which the heterocyclic D ring was substituted with various amino groups. Several analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms. Certain amino-substituted analogs also exhibited improved aqueous solubility compared to the corresponding un-substituted heterocyclic D-ring analogs.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Oxazolidinone analogs bearing substituted piperidine or azetidine C-rings are described. Analogs with a methyl group at the 3-position of the azetidine ring or the 4-position of the piperidine ring exhibited reduced mitochondrial protein synthesis inhibition while retaining good antibacterial potency.
Assuntos
Antibacterianos/farmacologia , Mitocôndrias/metabolismo , Oxazolidinonas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Antibacterianos/química , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oxazolidinonas/química , Inibidores da Síntese de Proteínas/química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Pirazóis/farmacologia , Estrutura Molecular , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
A new class of oxazolidinone antibacterials incorporating oxygen-, nitrogen-, or sulfur-containing heterobicyclic C-rings is described. The in vitro potency and in vivo efficacy of these conformationally constrained oxazolidinone analogs are discussed.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Compostos Aza/química , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Compostos de Sulfidrila/química , Amidas/química , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Compostos Aza/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Camundongos , Conformação Molecular , Oxazolidinonas/química , Oxazolidinonas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.