Syntheses and Structure–Activity Relationships of <i>N</i>-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome <i>bd</i> Oxidase in <i>Mycobacterium tuberculosis</i>

Abstract

The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.

Keywords

• tuberculosis
• drug development
• structure–activity relationships
• quinazoline
• energy metabolism
• cytochrome <i>bd</i> oxidase