Syntheses and structure–activity relationships of N-phenethyl-quinazolin-4-yl-amines as potent inhibitors of cytochrome bd oxidase in Mycobacterium tuberculosis

• Main Authors: Hopfner, Sarah M., Lee, Bei Shi, Kalia, Nitin P., Miller Marvin J., Pethe, Kevin, Moraski, Garrett C.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Biological sciences; Tuberculosis; Drug Development
• Online Access: https://hdl.handle.net/10356/153933
• Institution: Nanyang Technological University

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.