Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives.

Abstract

Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14,000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.

• Authors: Minghao Xu, Junsheng Zhu, Yanyan Diao, Hongchang Zhou, Xiaoli Ren, Deheng Sun, Jin Huang, Dongmei Han, Zhenjiang Zhao, Lili Zhu, Yufang Xu, Honglin Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 20 Pg. 7911-24 (Oct 24 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 24073986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Dihydroorotate Dehydrogenase
• Enzyme Inhibitors
• Furans
• Protozoan Proteins
• ethyl 2-(naphthalen-2-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
• 2-Naphthylamine
• Oxidoreductases Acting on CH-CH Group Donors

Topics

• 2-Naphthylamine (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Animals
• Antimalarials (chemistry, pharmacokinetics, pharmacology)
• Area Under Curve
• Dihydroorotate Dehydrogenase
• Drug Discovery
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Furans (chemistry, pharmacokinetics, pharmacology)
• Host-Parasite Interactions (drug effects)
• Humans
• Malaria, Falciparum (parasitology, prevention & control)
• Male
• Models, Chemical
• Molecular Structure
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, metabolism)
• Plasmodium falciparum (drug effects, enzymology, physiology)
• Protozoan Proteins (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley