Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase. / Hampton, Shahienaz E.; Baragana, Beatriz; Schipani, Alessandro; Bosch-Navarrete, Cristina; Alexander Musso-Buendia, J.; Recio, Eliseo; Kaiser, Marcel; Whittingham, Jean L.; Roberts, Shirley M.; Shevtsov, Mikhail; Brannigan, James A.; Kahnberg, Pia; Brun, Reto; Wilson, Keith S.; Gonzalez-Pacanowska, Dolores; Johansson, Nils Gunnar; Gilbert, Ian H.
In: ChemMedChem, Vol. 6, No. 10, 04.10.2011, p. 1816-1831.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase
A1 - Hampton,Shahienaz E.
A1 - Baragana,Beatriz
A1 - Schipani,Alessandro
A1 - Bosch-Navarrete,Cristina
A1 - Alexander Musso-Buendia,J.
A1 - Recio,Eliseo
A1 - Kaiser,Marcel
A1 - Whittingham,Jean L.
A1 - Roberts,Shirley M.
A1 - Shevtsov,Mikhail
A1 - Brannigan,James A.
A1 - Kahnberg,Pia
A1 - Brun,Reto
A1 - Wilson,Keith S.
A1 - Gonzalez-Pacanowska,Dolores
A1 - Johansson,Nils Gunnar
A1 - Gilbert,Ian H.
AU - Hampton,Shahienaz E.
AU - Baragana,Beatriz
AU - Schipani,Alessandro
AU - Bosch-Navarrete,Cristina
AU - Alexander Musso-Buendia,J.
AU - Recio,Eliseo
AU - Kaiser,Marcel
AU - Whittingham,Jean L.
AU - Roberts,Shirley M.
AU - Shevtsov,Mikhail
AU - Brannigan,James A.
AU - Kahnberg,Pia
AU - Brun,Reto
AU - Wilson,Keith S.
AU - Gonzalez-Pacanowska,Dolores
AU - Johansson,Nils Gunnar
AU - Gilbert,Ian H.
PY - 2011/10/4
Y1 - 2011/10/4
N2 - <p>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.</p>
AB - <p>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.</p>
KW - antiprotozoal agents
KW - drug design
KW - dUTPase
KW - malaria
KW - nucleosides
KW - DRUG
KW - TARGET
U2 - 10.1002/cmdc.201100255
DO - 10.1002/cmdc.201100255
M1 - Article
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 10
VL - 6
SP - 1816
EP - 1831
ER -