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Development of a novel drug for uncomplicated malaria targeting the mitochondrial NADH:quinone oxidoreductase

  • Giancarlo A Biagini1,
  • Alasdair Hill1,
  • Alison Mbekeani1,
  • Alison Shone1,
  • Gemma Nixon1,
  • Paul Stocks1,
  • Peter Gibbons2,
  • Richard Amewu2,
  • David W Hong2,
  • Victoria Barton2,
  • Chandra Pidathala2,
  • James Chadwick2,
  • Louise Le Pensee2,
  • Ashley Warman1,
  • Raman Sharma2,
  • Nick Fisher1,
  • Neil G Berry2,
  • Paul M O'Neill2 and
  • Steve A Ward1
Malaria Journal20109(Suppl 2):O4

Published: 20 October 2010


MalariaPlasmodium FalciparumHigh Throughput ScreeningHuman Liver MicrosomeUncomplicated Malaria

NADH:quinone oxidoreductase (PfNDH2) represents a metabolic choke point in the respiratory chain of Plasmodium falciparum mitochondria and is the focus of a drug discovery programme. A miniaturised assay for recombinant PfNDH2 with robust assay performance measures was generated for the high throughput screening (HTS) of a focused library of 17,000 drug-like compounds. A quantitative structure-activity relationship has been developed around one of the chemical templates derived from the HTS hits. Lead molecules developed to date show selective inhibitory activity against PfNDH2 versus P. falciparum bc1 or dihydroorotate dehydrogenase (DHODH). Potent enzyme inhibition is accompanied by in vitro parasite kill of multidrug-resistant strains in the low nM range and clearance of parasites from in vivo P. berghei models. Lead molecules also display excellent in vitro therapeutic indices against human cell lines and bovine bc1. Initial metabolic studies in human liver microsomes and hepatocytes indicate favourable pharmacology. These data support the further development of this new candidate drug targeting a novel parasite component.

Authors’ Affiliations

Liverpool School of Tropical Medicine, Liverpool, UK
Department of Chemistry, Liverpool University, Liverpool, UK


© Biagini et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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