Syntheses and Structure-Activity Relationships of N -Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis .

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:aa 3 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.