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

1
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
2
Department of Microbiology, Medical School of Huzhou Teachers College, Huzhou 313000, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2018, 23(6), 1254; https://doi.org/10.3390/molecules23061254
Received: 2 May 2018 / Revised: 21 May 2018 / Accepted: 22 May 2018 / Published: 24 May 2018
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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. View Full-Text
Keywords: P. falciparum; PfDHODH; pyrimidone; antimalarial agents P. falciparum; PfDHODH; pyrimidone; antimalarial agents
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Xu, L.; Li, W.; Diao, Y.; Sun, H.; Li, H.; Zhu, L.; Zhou, H.; Zhao, Z. Synthesis, Design, and Structure–Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase. Molecules 2018, 23, 1254.

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