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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.