Beta-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase

Baragana, B. and McCarthy, O. and Sanchez, P. and Bosch-Navarrete C., and Kaiser, M. and Brun, R. and Whittingham, J. L. and Roberts, S. M. and Zhou, X. X. and Wilson, K. S. and Johansson, N. G. and Gonzalez-Pacanowska D., and Gilbert, I. H.. (2011) Beta-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. Bioorganic & medicinal chemistry : a Tetrahedron publication for the rapid dissemenination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines, 19 (7). pp. 2378-2391.

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Official URL: http://edoc.unibas.ch/dok/A6002125

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We report a series of beta-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. beta-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K(i) of 0.5muM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC(50) 0.6muM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Dec 2017 14:00
Deposited On:08 Nov 2012 16:09

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