Synthesis, Design, and Structure⁻Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.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.  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.
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