Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials

Huaqing Cui, Juana Carrero-Lérida, Ana P G Silva, Jean L Whittingham, James A Brannigan, Luis M Ruiz-Pérez, Kevin D Read, Keith S Wilson (Lead / Corresponding author), Dolores González-Pacanowska (Lead / Corresponding author), Ian H Gilbert (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-a-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-a- and ß-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-a-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 µM).
    Original languageEnglish
    Pages (from-to)10948-57
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Volume55
    Issue number24
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    Antimalarials
    Thymidine
    dTMP kinase
    Urea
    Pyrimidine Nucleotides
    Enzyme Inhibitors
    Plasmodium falciparum
    Mycobacterium tuberculosis
    Parasites
    Enzymes
    Growth

    Cite this

    Cui, H., Carrero-Lérida, J., Silva, A. P. G., Whittingham, J. L., Brannigan, J. A., Ruiz-Pérez, L. M., ... Gilbert, I. H. (2012). Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials. Journal of Medicinal Chemistry, 55(24), 10948-57. https://doi.org/10.1021/jm301328h
    Cui, Huaqing ; Carrero-Lérida, Juana ; Silva, Ana P G ; Whittingham, Jean L ; Brannigan, James A ; Ruiz-Pérez, Luis M ; Read, Kevin D ; Wilson, Keith S ; González-Pacanowska, Dolores ; Gilbert, Ian H. / Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 24. pp. 10948-57.
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    abstract = "Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-a-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-a- and {\ss}-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-a-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 µM).",
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    Cui, H, Carrero-Lérida, J, Silva, APG, Whittingham, JL, Brannigan, JA, Ruiz-Pérez, LM, Read, KD, Wilson, KS, González-Pacanowska, D & Gilbert, IH 2012, 'Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials', Journal of Medicinal Chemistry, vol. 55, no. 24, pp. 10948-57. https://doi.org/10.1021/jm301328h

    Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials. / Cui, Huaqing; Carrero-Lérida, Juana; Silva, Ana P G; Whittingham, Jean L; Brannigan, James A; Ruiz-Pérez, Luis M; Read, Kevin D; Wilson, Keith S (Lead / Corresponding author); González-Pacanowska, Dolores (Lead / Corresponding author); Gilbert, Ian H (Lead / Corresponding author).

    In: Journal of Medicinal Chemistry, Vol. 55, No. 24, 2012, p. 10948-57.

    Research output: Contribution to journalArticle

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    AU - Ruiz-Pérez, Luis M

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    AU - Wilson, Keith S

    AU - González-Pacanowska, Dolores

    AU - Gilbert, Ian H

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    AB - Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-a-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-a- and ß-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-a-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 µM).

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    Cui H, Carrero-Lérida J, Silva APG, Whittingham JL, Brannigan JA, Ruiz-Pérez LM et al. Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials. Journal of Medicinal Chemistry. 2012;55(24):10948-57. https://doi.org/10.1021/jm301328h