RESUMO
High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes). In an effort to improve the activity of this active compound, a series of 2-substituted quinazolines was synthesized and evaluated in several antibacterial assays. One such compound (22) displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains. This molecule also inhibited transcription/translation of bacterial RNA, suggesting a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some of these molecules were found to be active in bacterial growth assays, none were as potent as 22. Compound 22 was tested for its ability to cure a systemic K. pneumonia infection in the mouse and displayed moderate effects compared with a control antibiotic, gentamycin.
Assuntos
Antibacterianos/síntese química , Benzoatos/síntese química , Quinazolinas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Biossíntese de Proteínas/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , RNA Bacteriano/genética , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacosRESUMO
Capillary electrophoresis has been applied to monitor model reactions in solution-phase combinatorial chemistry. In particular, the simultaneous alkylation reactions of secondary amines with a series of benzyl halides has been investigated. Reactant and product concentrations were monitored using capillary electrophoresis in a non-aqueous buffer system. The simplified sample preparation was a key feature making this an attractive method of analysis. The results demonstrate that capillary electrophoresis is a useful tool for monitoring reactions to determine initial rates, rate constants, and extinction correlation coefficients for quantitative analysis in combinatorial chemistry, and is a broadly applicable technique for the analysis of a variety of organic and bioorganic transformations.
Assuntos
Aminas/análise , Eletroforese Capilar/métodos , Acetamidas/química , Alquilação , Aminas/química , Compostos de Benzil/química , Compostos de Bromo/química , Cinética , Piperazinas/síntese químicaRESUMO
Several piperazine libraries were prepared using solution phase simultaneous addition of functionalities methodology as well as the "library from library" concept. The resulting piperazine libraries displayed antimicrobial activity against both gram-positive and gram-negative bacteria.
