Quinolinyl OxyAcetamide Dearivative for TB 2016

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

                                           

 

Narisa Phummarin,^a   Helena I. Boshoff,^b   Patricia S. Tsang,^b   James Dalton,^c   Siouxsie Wiles,^cd   Clifton E. Barry 3rd^b and   Brent R. Copp*^a  

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Corresponding authors

^a

School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
E-mail: b.copp@auckland.ac.nz
Fax: +64 9 3737422
Tel: +64 9 3737599

^b

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, USA

^c

Bioluminescent Superbugs Lab, Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

^d

Te Pūnaha Matatini, c/o University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00236F
Received 28 Apr 2016, Accepted 17 Aug 2016
First published online 22 Aug 2016

                                                                           

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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.