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Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase. 2011
Gian Filippo Ruda, and
Corinne Nguyen, and
Przemysław Ziemkowski, and
Krzysztof Felczak, and
Ganasan Kasinathan, and
Alexander Musso-Buendia, and
Christian Sund, and
Xiao Xiong Zhou, and
Marcel Kaiser, and
Luis M Ruiz-Pérez, and
Reto Brun, and
Tadeusz Kulikowski, and
Nils Gunnar Johansson, and
Dolores González-Pacanowska, and
Ian H Gilbert
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
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.
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