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Design, Synthesis, and Evaluation of 5'-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase

DOI: 10.1002/cmdc.201100255 DOI Help

Authors: Shahienaz E. Hampton (University of Dundee, U.K.) , Beatriz Baragaña (University of Dundee, U.K.) , Alessandro Schipani (University of Dundee, U.K.) , Cristina Bosch-navarrete (Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, Spain) , J. Alexander Musso-buendía (Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, Spain) , Eliseo Recio (Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, Spain) , Marcel Kaiser (Swiss Tropical and Public Health Institute, Switzerland) , Jean L. Whittingham (University of York, U.K.) , Shirley M. Roberts (University of York, U.K.) , Mikhail Shevtsov (University of York, U.K.) , James A. Brannigan (University of York) , Pia Kahnberg (Medivir AB, Sweden) , Reto Brun (Swiss Tropical and Public Health Institute, Spain) , Keith S. Wilson (University of York, U.K.) , Dolores González-pacanowska (Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, Spain) , Nils Gunnar Johansson (Medivir AB, Sweden) , Ian H. Gilbert (University of Dundee, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 6 (10) , PAGES 1816 - 1831

State: Published (Approved)
Published: October 2011
Diamond Proposal Number(s): 1221

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

Journal Keywords: Antiprotozoal Agents; Drug Design; Dutpase; Malaria; Nucleosides

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF ID231

Added On: 26/09/2012 13:59

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