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Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
1022991
Author(s)
Ruda, Gian Filippo; Nguyen, Corinne; Ziemkowski, Przemysław; Felczak, Krzysztof; Kasinathan, Ganasan; Musso-Buendia, Alexander; Sund, Christian; Zhou, Xiao Xiong; Kaiser, Marcel; Ruiz-Pérez, Luis M; Brun, Reto; Kulikowski, Tadeusz; Johansson, Nils Gunnar; González-Pacanowska, Dolores; Gilbert, Ian H
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
