RESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Toxinas Bacterianas/antagonistas & inibidores , Benzodiazepinas/química , Administração Oral , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Benzodiazepinas/farmacocinética , Benzodiazepinas/uso terapêutico , Células CHO , Clostridioides difficile/metabolismo , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/veterinária , Cricetinae , Cricetulus , Meia-Vida , Camundongos , Relação Estrutura-AtividadeRESUMO
The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50â¯=â¯0.77⯵M). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50â¯=â¯1â¯nM) and 13â¯l(IC50â¯=â¯7â¯nM) which were chosen as leads for further optimization.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Toxinas Bacterianas/antagonistas & inibidores , Clostridioides difficile/efeitos dos fármacos , Nucleotidases/antagonistas & inibidores , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Apoptose/efeitos dos fármacos , Células CHO , Cricetulus , Estabilidade de Medicamentos , Enterotoxinas/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.
Assuntos
Antibacterianos/síntese química , Quinolonas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Eritromicina/síntese química , Eritromicina/farmacologia , Eritromicina/análogos & derivados , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
A series of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives has been synthesized. Several functional groups were identified as the optimal C3-substituents, and the best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
