TY - JOUR
T1 - Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites
AU - Beteck, Richard M.
AU - Seldon, Ronnett
AU - Coertzen, Dina
AU - van der Watt, Mariëtte E.
AU - Reader, Janette
AU - Mackenzie, Jared S.
AU - Lamprecht, Dirk A.
AU - Abraham, Matthew
AU - Eribez, Korina
AU - Müller, Joachim
AU - Rui, Feng
AU - Zhu, Guang
AU - de Grano, Ruel Valerio
AU - Williams, Ian D.
AU - Smit, Frans J.
AU - Steyn, Adrie J.C.
AU - Winzeler, Elizabeth A.
AU - Hemphill, Andrew
AU - Birkholtz, Lyn Marie
AU - Warner, Digby F.
AU - N’Da, David D.
AU - Haynes, Richard K.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42004-018-0062-7
DO - 10.1038/s42004-018-0062-7
M3 - Article
AN - SCOPUS:85062074115
SN - 2399-3669
VL - 1
SP - 1
EP - 11
JO - Communications Chemistry
JF - Communications Chemistry
IS - 1
M1 - 62
ER -