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)

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    36 Citations (Scopus)


    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
    Issue number24
    Publication statusPublished - 2012


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