Acyclic Nucleoside Analogues as Inhibitors of Plasmodium falciparum dUTPase

We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assay...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (14), p.4183-4195
Main Authors: NGUYEN, Corinne, RUDA, Gian Filippo, SCHIPANI, Alessandro, KASINATHAN, Ganasan, LEAL, Isabel, MUSSO-BUENDIA, Alexander, KAISER, Marcel, BRUN, Reto, RUIZ-PéREZ, Luis M., SAHLBERG, Britt-Louise, JOHANSSON, Nils Gunnar, GONZáLEZ-PACANOWSKA, Dolores, GILBERT, Ian H.
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemical synthesis
Antimalarials - pharmacology
Antiparasitic agents
Biological and medical sciences
Erythrocytes - drug effects
Erythrocytes - parasitology
Humans
In Vitro Techniques
Medical sciences
Models, Molecular
Nucleosides - chemical synthesis
Nucleosides - pharmacology
Pharmacology. Drug treatments
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Pyrophosphatases - antagonists & inhibitors
Pyrophosphatases - chemistry
Stereoisomerism
Structure-Activity Relationship
Trityl Compounds - chemical synthesis
Trityl Compounds - pharmacology
Uracil - analogs & derivatives
Uracil - chemical synthesis
Uracil - pharmacology
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Summary:We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assayed against both P.falciparum dUTPase and intact parasites. A good correlation was observed between enzyme inhibition and cellular assays. Acyclic uracil derivatives were identified that showed greater or similar potency and in general increased selectivity compared to previously reported inhibitors. The most active compound reported here against the P. falciparum enzyme had a K(i) of 0.2 microM. Molecular modeling studies provided a good rationale for the observed activities. Preliminary ADME studies indicated that some of the lead compounds are drug-like molecules. These compounds are useful tools for further investigating P. falciparum dUTPase for the development of much-needed novel antimalarial drugs.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060126s