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: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.
Highlights
Accepted: 22 September 2021Tuberculosis (TB) is still a leading cause of death from an infectious agent
Our initial efforts were to probe the effect of alteration and modification of the phenethylaniline moiety around a fixed quinazoline core
This was done by syntheses of 10 compounds and screening against M. bovis BCG and Mycobacterium tuberculosis (Mtb) strains (H37Rv and N0145) to assess activity against mycobacterial cyt-bd (Table 1)
Summary
Tuberculosis (TB) is still a leading cause of death from an infectious agent. According to the World Health Organization’s 2020 Global Tuberculosis Report, over 10 million people became ill with the disease in 2019 [1]. Action must be taken to combat this continuing public health threat. TB is caused by the bacterium Mycobacterium tuberculosis (Mtb) and spread by aerosols of an infected person through a cough or sneeze. Treatment of individuals infected with TB consists of several medications that are taken together for. First-line drugs include isoniazid (INH), rifampin (RIF), ethambutol (EMB)
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