Abstract
The inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) potentially represents a new treatment option for malaria, as P. falciparum relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of PfDHODH. The most potent compound, 26, showed high inhibition activity against PfDHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (hDHODH). The brand-new inhibitor scaffold targeting PfDHODH reported in this work may lead to the discovery of new antimalarial agents.
Keywords:
P. falciparum; PfDHODH; antimalarial agents; pyrimidone.
MeSH terms
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Dihydroorotate Dehydrogenase
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Models, Molecular
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Molecular Structure
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Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
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Oxidoreductases Acting on CH-CH Group Donors / chemistry
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology
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Species Specificity
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Structure-Activity Relationship
Substances
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Dihydroorotate Dehydrogenase
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Enzyme Inhibitors
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Protozoan Proteins
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Pyrimidinones
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Oxidoreductases Acting on CH-CH Group Donors