Structure-activity relationships of novel 2-substituted quinazoline antibacterial agents

High-throughput screening of in-house compound libraries led to the discove ry of a novel antibacterial agent, compound 1 (MIC: 12-25 mu M against S. p yogenes). In an effort to improve the activity of this active compound, a s eries of 2-substituted quinazolines was synthesized and evaluated in severa l antibacterial assays. One such compound (22) displayed improved broad-spe ctrum antibacterial activity against a variety of bacterial strains. This m olecule also inhibited transcription/translation of bacterial RNA, suggesti ng a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some o f 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 syst emic K. pneumonia infection in the mouse and displayed moderate effects com pared with a control antibiotic, gentamycin.