RESUMO
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Piperidinas/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Haplorrinos , Infusões Intravenosas , Masculino , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Ratos , Ratos Sprague-Dawley , Solubilidade , EstereoisomerismoRESUMO
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Acrilatos/farmacologia , Estabilidade de Medicamentos , Isomerismo , Testes de Sensibilidade Microbiana , Fotoquímica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Proteínas de Transporte/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/fisiologia , Pirimidinas/química , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Ligação Proteica/fisiologia , Pseudomonas aeruginosa/química , Pirimidinas/metabolismoRESUMO
A total synthesis of the threo/trans/erythro-type acetogenin mosin B and one of its diastereomers has been achieved. The carbon skeleton is assembled in a convergent fashion from two segments (a THF ring segment and a gamma-lactone segment) through the Nozaki-Hiyama-Kishi reaction. The THF ring segment was stereoselectively constructed by a stereodivergent synthesis starting from a common intermediate (4-cyclohexene-1,2-diol) based on a desymmetrization strategy. The gamma-lactone segment was synthesized by coupling a triflate and a chiral alpha-sulfenyl gamma-lactone. By virtue of these synthetic results, we suggest that the absolute configuration of natural mosin B is 1 a. Antiproliferative effects of 1 a and 1 b were also investigated.