RESUMO
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
Assuntos
Antituberculosos/síntese química , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/química , Pirimidinas/síntese química , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/sangue , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Modelos Animais de Doenças , Estabilidade de Medicamentos , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Nitroimidazóis/sangue , Nitroimidazóis/farmacocinética , Nitroimidazóis/farmacologia , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Solubilidade , Relação Estrutura-Atividade , Tuberculose/sangue , Tuberculose/microbiologiaRESUMO
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolonas/farmacologia , Inibidores da Topoisomerase/farmacologia , HumanosRESUMO
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
Assuntos
Acetamidas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Piridinas/química , Antibacterianos/química , Enterococcus/efeitos dos fármacos , Linezolida , Estrutura Molecular , Oxazolidinonas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
