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Design, Synthesis, and Evaluation of 5′‐Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase
Author(s) -
Hampton Shahienaz E.,
Baragaña Beatriz,
Schipani Alessandro,
BoschNavarrete Cristina,
MussoBuendía J. Alexander,
Recio Eliseo,
Kaiser Marcel,
Whittingham Jean L.,
Roberts Shirley M.,
Shevtsov Mikhail,
Brannigan James A.,
Kahnberg Pia,
Brun Reto,
Wilson Keith S.,
GonzálezPacanowska Dolores,
Johansson Nils Gunnar,
Gilbert Ian H.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100255
Subject(s) - moiety , lipophilicity , plasmodium falciparum , chemistry , stereochemistry , deoxyuridine , lead compound , nucleoside , combinatorial chemistry , biochemistry , in vitro , dna , malaria , biology , immunology
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 Pf dUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.