Abstract
The bifunctional enzyme N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP(+) and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Humans
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Leukemia / drug therapy
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Macrophages / drug effects
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Methylenetetrahydrofolate Dehydrogenase (NADP) / antagonists & inhibitors
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Methylenetetrahydrofolate Dehydrogenase (NADP) / chemistry
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Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism
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Models, Molecular
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / pharmacology*
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / pharmacology*
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects*
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Trypanosoma brucei brucei / enzymology
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Trypanosoma brucei brucei / growth & development
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Trypanosomiasis, African / drug therapy
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Trypanosomiasis, African / parasitology
Substances
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Enzyme Inhibitors
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Phenylurea Compounds
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Pyrimidinones
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Trypanocidal Agents
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Methylenetetrahydrofolate Dehydrogenase (NADP)