Structure−Activity Relationships of Novel 2-Substituted Quinazoline Antibacterial Agents

TLDR

The study aimed to improve the activity of a lead antibacterial compound by synthesizing and testing a series of 2‑substituted quinazolines. The authors synthesized a series of 2‑substituted quinazolines, performed structure‑activity relationship studies, and evaluated the lead compound in vitro and in a mouse model of K. pneumonia infection.

Abstract

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.