Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase |
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Authors: | Ruda Gian Filippo Nguyen Corinne Ziemkowski Przemys?aw 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 |
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Affiliation: | Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK. |
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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. |
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