SAR and identification of 2-(quinolin-4-yloxy)acetamides asMycobacterium tuberculosiscytochromebc1inhibitors.
A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors ofMycobacterium 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 cytochromebdoxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of theqcrBgene, 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 theM. tuberculosis bc1complex.
School of Chemical Sciences , University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand . Email: b.copp@auckland.ac.nz ; ; Tel: +64 9 3737599.
Narisa
N
Phummarin
Tuberculosis Research Section , Laboratory of Clinical Infectious Diseases , National Institute of Allergy and Infectious Disease , National Institutes of Health , Bethesda , Maryland , USA.
Helena I
HI
Boshoff
Tuberculosis Research Section , Laboratory of Clinical Infectious Diseases , National Institute of Allergy and Infectious Disease , National Institutes of Health , Bethesda , Maryland , USA.
Patricia S
PS
Tsang
Bioluminescent Superbugs Lab , Department of Molecular Medicine and Pathology , University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand.
James
J
Dalton
Bioluminescent Superbugs Lab , Department of Molecular Medicine and Pathology , University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand ; Te Pūnaha Matatini , c/o University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand.
Siouxsie
S
Wiles
Tuberculosis Research Section , Laboratory of Clinical Infectious Diseases , National Institute of Allergy and Infectious Disease , National Institutes of Health , Bethesda , Maryland , USA.
Clifton E
CE
Barry Rd
School of Chemical Sciences , University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand . Email: b.copp@auckland.ac.nz ; ; Tel: +64 9 3737599.
Brent R
BR
Copp