Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Richard M. Beteck, Ronnett Seldon, Dina Coertzen, Mariëtte E. van der Watt, Janette Reader, Jared S. Mackenzie, Dirk A. Lamprecht, Matthew Abraham, Korina Eribez, Joachim Müller, Feng Rui, Guang Zhu, Ruel Valerio de Grano, Ian D. Williams, Frans J. Smit, Adrie J.C. Steyn, Elizabeth A. Winzeler, Andrew Hemphill, Lyn Marie Birkholtz, Digby F. WarnerDavid D. N’Da, Richard K. Haynes

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Article number62
Pages (from-to)1-11
Number of pages11
JournalCommunications Chemistry
Volume1
Issue number1
Early online date02 Oct 2018
DOIs
Publication statusPublished - 01 Dec 2018

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