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SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc₁ inhibitors.

ABSTRACT: A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (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 bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc₁) 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 M. tuberculosis bc₁ complex.

SUBMITTER: Phummarin N

PROVIDER: S-EPMC5292992 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors.

Phummarin Narisa N Boshoff Helena I HI Tsang Patricia S PS Dalton James J Wiles Siouxsie S Barry Rd Clifton E CE Copp Brent R BR

MedChemComm 20160822 11

A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (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 bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB</ ...[more]

PMID: 28337336

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