Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites
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Date
2018Author
Beteck, Richard M.
Smit, Frans J.
N'Da, David D.
Haynes, Richard K.
Seldon, Ronnett
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The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity is often not adequately exploited due to poor physicochemical properties. Here we convert decoquinate into N-alkyl quinolone amides that, in contrast to decoquinate, are active against the tuberculosis bacterium with MIC90 values ranging from 1.4 to 3.64 µM, and quinoline O-carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC50 values of 0.32–1.5 nM for the best derivative. Uniquely for the TB-active amides, disruption of cell wall homoeostasis is identified as one target. With IC50 values against fetal lung fibroblast cells of 40 to >100 μM, the derivatives are selective for the pathogens. Structures of the most active derivatives are determined by NMR spectroscopy and X-ray crystallography. Analogues lacking the decyl side chain of decoquinate are inactive
URI
http://hdl.handle.net/10394/31566https://www.nature.com/articles/s42004-018-0062-7
https://doi.org/10.1038/s42004-018-0062-7
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- Faculty of Health Sciences [2386]