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Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials

[Image: see text] Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesi...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530961/
https://www.ncbi.nlm.nih.gov/pubmed/23240776
http://dx.doi.org/10.1021/jm301328h
Descripción
Sumario:[Image: see text] Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-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-α- and β-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-α-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).