SAR and identification of 2-(quinolin-4-yloxy)acetamides as <i>Mycobacterium tuberculosis</i> cytochrome <i>bc</i><sub>1</sub> inhibitors.
Phummarin N, Boshoff HI, Tsang PS, Dalton J, Wiles S, Barry Rd CE, Copp BR.
A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of <i>Mycobacterium tuberculosis</i> (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome <i>bd</i> oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the <i>qcrB</i> gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (<i>bc</i><sub>1</sub>) complex, were resistant to the library. These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the <i>M. tuberculosis bc</i><sub>1</sub> complex.