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

Shahienaz E. Hampton; Beatriz Baragana; Alessandro Schipani; Cristina Bosch-Navarrete; J. Alexander Musso-Buendia; Eliseo Recio; Marcel Kaiser; Jean L. Whittingham; Shirley M. Roberts; Mikhail Shevtsov; James A. Brannigan; Pia Kahnberg; Reto Brun; Keith S. Wilson; Dolores Gonzalez-Pacanowska; Nils Gunnar Johansson; Ian H. Gilbert

doi:10.1002/cmdc.201100255

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

Shahienaz E. Hampton, Beatriz Baragana, Alessandro Schipani, Cristina Bosch-Navarrete, J. Alexander Musso-Buendia, Eliseo Recio, Marcel Kaiser, Jean L. Whittingham, Shirley M. Roberts, Mikhail Shevtsov, James A. Brannigan, Pia Kahnberg, Reto Brun, Keith S. Wilson, Dolores Gonzalez-Pacanowska, Nils Gunnar Johansson, Ian H. Gilbert

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1816-1831
Number of pages	16
Journal	ChemMedChem
Volume	6
Issue number	10
DOIs	https://doi.org/10.1002/cmdc.201100255
Publication status	Published - 4 Oct 2011

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Hampton, S. E., Baragana, B., Schipani, A., Bosch-Navarrete, C., Alexander Musso-Buendia, J., Recio, E., Kaiser, M., Whittingham, J. L., Roberts, S. M., Shevtsov, M., Brannigan, J. A., Kahnberg, P., Brun, R., Wilson, K. S., Gonzalez-Pacanowska, D., Johansson, N. G., & Gilbert, I. H. (2011). Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase. ChemMedChem, 6(10), 1816-1831. https://doi.org/10.1002/cmdc.201100255

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

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.",

author = "Hampton, {Shahienaz E.} and Beatriz Baragana and Alessandro Schipani and Cristina Bosch-Navarrete and {Alexander Musso-Buendia}, J. and Eliseo Recio and Marcel Kaiser and Whittingham, {Jean L.} and Roberts, {Shirley M.} and Mikhail Shevtsov and Brannigan, {James A.} and Pia Kahnberg and Reto Brun and Wilson, {Keith S.} and Dolores Gonzalez-Pacanowska and Johansson, {Nils Gunnar} and Gilbert, {Ian H.}",

year = "2011",

month = oct,

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doi = "10.1002/cmdc.201100255",

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Hampton, SE, Baragana, B, Schipani, A, Bosch-Navarrete, C, Alexander Musso-Buendia, J, Recio, E, Kaiser, M, Whittingham, JL, Roberts, SM, Shevtsov, M, Brannigan, JA, Kahnberg, P, Brun, R, Wilson, KS, Gonzalez-Pacanowska, D, Johansson, NG & Gilbert, IH 2011, 'Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase', ChemMedChem, vol. 6, no. 10, pp. 1816-1831. https://doi.org/10.1002/cmdc.201100255

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T1 - Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase

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 - 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.

AB - 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.

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JO - ChemMedChem

JF - ChemMedChem

IS - 10

ER -

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

Abstract

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