Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase
| Autor: | Marcel Kaiser, Dolores Gonzalez Pacanowska, Alex Musso-Buendia, Ian H. Gilbert, Reto Brun, Luis M. Ruiz-Pérez, Orla McCarthy, Nils Gunnar Johansson |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Plasmodium falciparum Structure-Activity Relationship chemistry.chemical_compound DUTP pyrophosphatase Acetamides Drug Discovery Animals Enzyme Inhibitors Pyrophosphatases Uracil Pharmacology chemistry.chemical_classification biology Organic Chemistry General Medicine biology.organism_classification Enzyme Biochemistry chemistry Enzyme inhibitor Drug Design biology.protein DNA fragmentation DNA Acetamide |
| Zdroj: | European Journal of Medicinal Chemistry. 44:678-688 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2008.05.018 |
| Popis: | The ubiquitous enzyme dUTP nucleotidohydrolase (dUTPase) catalyses the hydrolysis of dUTP to dUMP and can be considered as the first line of defence against incorporation of uracil into DNA. Inhibition of this enzyme results in over-incorporation of uracil into DNA, leading to DNA fragmentation and cell death and is therefore lethal. By taking advantage of structural differences between the human and Plasmodium dUTPase, selective inhibitors of the enzyme can be designed and synthesised with the aim of being developed into novel anti-parasitic drugs. Analogue based design was used to target the Plasmodium falciparum dUTPase (PfdUTPase). The structures of previously discovered selective inhibitors of the PfdUTPase were modified by insertion of an amide bond. A series of tritylated uracil acetamide derivatives were synthesised and assessed for inhibition of the enzyme and parasite growth in vitro. These compounds were weak inhibitors of the PfdUTPase. |
| Databáze: | OpenAIRE |
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