β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase

We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5′-triphosphate nucleotidohydrolase ( PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compo...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-04, Vol.19 (7), p.2378-2391
Main Authors: Baragaña, Beatriz, McCarthy, Orla, Sánchez, Paula, Bosch-Navarrete, Cristina, Kaiser, Marcel, Brun, Reto, Whittingham, Jean L., Roberts, Shirley M., Zhou, Xiao-Xiong, Wilson, Keith S., Johansson, Nils Gunnar, González-Pacanowska, Dolores, Gilbert, Ian H.
Format: Article
Language:English
Subjects:
active sites
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Biological and medical sciences
crystal structure
Deoxyuridine - analogs & derivatives
Deoxyuridine - chemistry
Deoxyuridine - pharmacology
DNA
dUTPase
enzyme inhibition
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
growth retardation
Humans
Medical sciences
metabolism
Models, Molecular
parasites
Pharmacology. Drug treatments
Plasmodium falciparum
Plasmodium falciparum - enzymology
Pyrophosphatases - antagonists & inhibitors
Structure-Activity Relationship
uracil
uridine
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Summary:We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5′-triphosphate nucleotidohydrolase ( PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. β-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K i of 0.5 μM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC 50 0.6 μM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.02.012