Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase |
| |
Authors: | Hampton Shahienaz E Baragaña Beatriz Schipani Alessandro Bosch-Navarrete Cristina Musso-Buendía J Alexander Recio Eliseo Kaiser Marcel Whittingham Jean L Roberts Shirley M Shevtsov Mikhail Brannigan James A Kahnberg Pia Brun Reto Wilson Keith S González-Pacanowska Dolores Johansson Nils Gunnar Gilbert Ian H |
| |
Affiliation: | Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK. |
| |
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. |
| |
Keywords: | antiprotozoal agents drug design dUTPase malaria nucleosides |
本文献已被 PubMed 等数据库收录! |
|