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
A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.
Assuntos
Hepacivirus/enzimologia , Piridinas/química , Piridinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Cães , Hepacivirus/efeitos dos fármacos , Humanos , Macaca fascicularis , Ratos , Relação Estrutura-AtividadeRESUMO
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 novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.
Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Piridinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Hepacivirus/genética , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/genéticaRESUMO
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.