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

Academic Article

Abstract

  • © 2018, The Author(s). 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.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Beteck RM; Seldon R; Coertzen D; van der Watt ME; Reader J; Mackenzie JS; Lamprecht DA; Abraham M; Eribez K; Müller J
  • Volume

  • 1
  • Issue

  • 1