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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2012
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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 |
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author | 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. |
author_facet | 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. |
author_sort | Cui, Huaqing |
collection | PubMed |
description | [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). |
format | Online Article Text |
id | pubmed-3530961 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-35309612013-01-06 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. González-Pacanowska, Dolores Gilbert, Ian H. J Med Chem [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). American Chemical Society 2012-12-14 2012-12-27 /pmc/articles/PMC3530961/ /pubmed/23240776 http://dx.doi.org/10.1021/jm301328h Text en Copyright © 2012 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | 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 |
title | Synthesis and Evaluation
of α-Thymidine
Analogues as Novel Antimalarials |
title_full | Synthesis and Evaluation
of α-Thymidine
Analogues as Novel Antimalarials |
title_fullStr | Synthesis and Evaluation
of α-Thymidine
Analogues as Novel Antimalarials |
title_full_unstemmed | Synthesis and Evaluation
of α-Thymidine
Analogues as Novel Antimalarials |
title_short | Synthesis and Evaluation
of α-Thymidine
Analogues as Novel Antimalarials |
title_sort | synthesis and evaluation
of α-thymidine
analogues as novel antimalarials |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530961/ https://www.ncbi.nlm.nih.gov/pubmed/23240776 http://dx.doi.org/10.1021/jm301328h |
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