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Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase

McCarthy, O. and Musso-Buendia A., and Kaiser, M. and Brun, R. and Ruiz-Perez L. M., and Johansson, N. G. and Pacanowska, D. G. and Gilbert, I. H.. (2009) Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase. European journal of medicinal chemistry, Vol. 44, H. 2. S. 678-688.

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Official URL: http://edoc.unibas.ch/dok/A5843186

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Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0223-5234
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:17
Deposited On:14 Sep 2012 06:39

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