Abstract
Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-α-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 μM).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Blood Proteins / metabolism
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Cell Line
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Crystallography, X-Ray
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Humans
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Ligands
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Nucleoside-Phosphate Kinase / antagonists & inhibitors
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Nucleoside-Phosphate Kinase / chemistry
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology
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Protein Binding
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Thiourea / analogs & derivatives*
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Thiourea / chemical synthesis*
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Thiourea / pharmacology
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Thymidine / analogs & derivatives*
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Thymidine / chemical synthesis*
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Thymidine / pharmacology
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacology
Substances
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Antimalarials
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Blood Proteins
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Ligands
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Protozoan Proteins
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Recombinant Proteins
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Urea
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Nucleoside-Phosphate Kinase
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dTMP kinase
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Thiourea
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Thymidine