Artikel
Novel FAS II inhibitors as multistage antimalarials
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Autoren
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F. C. Schrader
- Institut für Pharmazeutische Chemie, Philips Universität Marburg, Germany
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S. Glinca
- Institut für Pharmazeutische Chemie, Philips Universität Marburg, Germany
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J. M. Sattler
- Dept. für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, Germany
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H. M. Dahse
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie – Hans-Knöll-Institut, Jena, Germany
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G. A. Afanador
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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S. T. Prigge
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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M. Lanzer
- Dept. für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, Germany
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A. K. Mueller
- Dept. für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, Germany
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G. Klebe
- Institut für Pharmazeutische Chemie, Philips Universität Marburg, Germany
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M. Schlitzer
- Institut für Pharmazeutische Chemie, Philips Universität Marburg, Germany
| Veröffentlicht: | 8. Januar 2013 |
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Gliederung
Text
In order to cure not only malaria but prevent transmission as well, a drug must target both, the blood-stage and the pre-erythrocytic stages of the parasite. PfENR is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of P. berghei and is therefore qualified as a target for true causal chemoprophylaxis. By virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds, which are effective against both pre-erythrocytic and blood-stage malaria parasites. Two of the most promising derivatives were found to inhibit multiple stages of Plasmodium. These compounds inhibit blood-stage parasite growth with IC50s of 1.7 and 3.0 µM and lead to a more prominent developmental attenuation of liver-stages than the standard primaquine. Both compounds display very low cytotoxicity (CC50 HeLa >80 µM).
