Lucumi Moreno, Edinson (2005-12). Structural determination of triclosan derivatives as inhibitors of Plasmodium falciparum enoyl reductase (PfENR). Master's Thesis. Thesis uri icon


  • Malaria is a disease that causes more than 1 million deaths per year world wide
    and more than 400 million clinical cases. Due to the acquired resistance of Plasmodium
    falciparum to the drugs used to control the infection, searching for new anti-malaria
    drugs is necessary in modern days. Recent studies have shown that the parasite
    synthesizes fatty acids using a fatty acid synthase type II (FAS-II) instead of a type-I fatty
    acid synthase (FAS-I) that is present in other eukaryotes. Plasmodium falciparum enoyl
    reductase (PfENR) is responsible for the last step of fatty acid biosynthesis in the
    parasite. This enzyme is located within the apicoplast, a plastid-like organelle that is
    responsible for several important metabolic pathways, including fatty acid biosynthesis. It
    is known that triclosan is an inhibitor of ENR in bacteria and we and others have shown
    that it is also effective against ENR in apicomplexan organisms such as P. falciparum.
    However triclosan cannot be used to treat malaria in humans because it has metabolic
    liability (glucoronidation) which limits its inhibitory potency. We have used X-ray crystallography and a Structural Activity Relationship (SAR) strategy to design and cocrystallize
    a tertiary complex of PfENR with NAD+ and triclosan derivatives to improve
    their properties as drugs to treat malaria. More than five hundred triclosan derivatives
    were synthesized, and their in vitro and in vivo inhibitory activity evaluated. Furthermore,
    structural studies were made of their affinity to interact with residues in PfENR active
    sites, as well as with the cofactor NAD+. A total of six PfENR-NAD+-triclosan
    analog/complexes structures were determined. Analogs which had replacements of
    chloride groups at position 5 of ring A and 4' of ring B were determined, allowing the
    structural analysis of the binding of these triclosan analogs to PfENR. In addition, the
    urea derivatives (modification at position 1) as well as phenylsulphonamides
    (modification at position 2') have shown to be more potent inhibitors than triclosan in the
    in vivo assay. The analysis of the inhibitory properties and the structure of these analogs
    bound to PfENR will provide novel compounds in the search for new anti-malarial drugs.

publication date

  • December 2005