Modified 5'-Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase

Gian Filippo Ruda, Corinne Nguyen, Przemysław Ziemkowski, Krzysztof Felczak, Ganasan Kasinathan, Alexander Musso-Buendia, Christian Sund, Xiao Xiong Zhou, Marcel Kaiser, Luis M. Ruiz-Pérez, Reto Brun, Tadeusz Kulikowski, Nils Gunnar Johansson, Dolores González-Pacanowska, Ian H. Gilbert

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. Fewer trips to the dUMP: dUTPase is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this P.falciparum enzyme. Herein we report further structure-activity studies of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.

Original languageEnglish (US)
Pages (from-to)309-320
Number of pages12
JournalChemMedChem
Volume6
Issue number2
DOIs
StatePublished - Feb 7 2011

Keywords

  • DUTPase
  • Malaria
  • Nucleoside chemistry
  • Nucleotide metabolism
  • Plasmodium falciparum

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