RESUMO
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , ortoaminobenzoatos/química , Antibacterianos/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Indazóis/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding has been previously reported. The structure-activity relationships around the carboxylic acid substituent are described herein. This acid was replaced by several alternative functional groups in attempts to retain bioactivity while reducing protein binding. Only groups with an acidic proton retained activity, and analogs containing those groups maintained the protein binding inherent to this class of antibacterial agents.
Assuntos
Bactérias/efeitos dos fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Bactérias/genética , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8mug/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of 1mug/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.
