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

The inhibition of <italic>Plasmodium falciparum</italic> dihydroorotate dehydrogenase (<italic>Pf</italic>DHODH) potentially represents a new treatment option for malaria, as <italic>P. falciparum</italic> relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of <italic>Pf</italic>DHODH. The most potent compound, <bold>26</bold>, showed high inhibition activity against <italic>Pf</italic>DHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (<italic>h</italic>DHODH). The brand-new inhibitor scaffold targeting <italic>Pf</italic>DHODH reported in this work may lead to the discovery of new antimalarial agents. [ABSTRACT FROM AUTHOR]