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

• Published in: ChemMedChem Vol. 6; no. 2; pp. 309 - 320
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.02.2011; WILEY‐VCH Verlag
• Subjects: Animals; dUTPase; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; malaria; nucleoside chemistry; Nucleosides - chemistry; Nucleosides - pharmacology; nucleotide metabolism; Plasmodium falciparum; Plasmodium falciparum - enzymology; Pyrophosphatases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000445

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.