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Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase

Hampton, S. E. and Baragana, B. and Schipani, A. and Bosch-Navarrete C., and Musso-Buendia J. A., and Recio, E. and Kaiser, M. and Whittingham, J. L. and Roberts, S. M. and Shevtsov, M. and Brannigan, J. A. and Kahnberg, P. and Brun, R. and Wilson, K. S. and Gonzalez-Pacanowska D., and Johansson, N. G. and Gilbert, I. H.. (2011) Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase. ChemMedChem : chemistry enabling drug discovery, Vol. 6, H. 10. S. 1816-1831.

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Official URL: http://edoc.unibas.ch/dok/A6002160

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Abstract

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel and Brun, Reto
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Wiley-VCH
ISSN:1860-7179
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:22
Deposited On:08 Nov 2012 16:09

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