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Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity
[Image: see text] The bifunctional enzyme N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the...
| Autores principales: | , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2015
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621507/ https://www.ncbi.nlm.nih.gov/pubmed/26322631 http://dx.doi.org/10.1021/acs.jmedchem.5b00687 |
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| author | Eadsforth, Thomas C. Pinto, Andrea Luciani, Rosaria Tamborini, Lucia Cullia, Gregorio De Micheli, Carlo Marinelli, Luciana Cosconati, Sandro Novellino, Ettore Lo Presti, Leonardo Cordeiro da Silva, Anabela Conti, Paola Hunter, William N. Costi, Maria P. |
| author_facet | Eadsforth, Thomas C. Pinto, Andrea Luciani, Rosaria Tamborini, Lucia Cullia, Gregorio De Micheli, Carlo Marinelli, Luciana Cosconati, Sandro Novellino, Ettore Lo Presti, Leonardo Cordeiro da Silva, Anabela Conti, Paola Hunter, William N. Costi, Maria P. |
| author_sort | Eadsforth, Thomas C. |
| collection | PubMed |
| description | [Image: see text] The bifunctional enzyme N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC(50) of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC(50) 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP(+) and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors. |
| format | Online Article Text |
| id | pubmed-4621507 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2015 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-46215072015-10-28 Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity Eadsforth, Thomas C. Pinto, Andrea Luciani, Rosaria Tamborini, Lucia Cullia, Gregorio De Micheli, Carlo Marinelli, Luciana Cosconati, Sandro Novellino, Ettore Lo Presti, Leonardo Cordeiro da Silva, Anabela Conti, Paola Hunter, William N. Costi, Maria P. J Med Chem [Image: see text] The bifunctional enzyme N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC(50) of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC(50) 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP(+) and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors. American Chemical Society 2015-08-31 2015-10-22 /pmc/articles/PMC4621507/ /pubmed/26322631 http://dx.doi.org/10.1021/acs.jmedchem.5b00687 Text en Copyright © 2015 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
| spellingShingle | Eadsforth, Thomas C. Pinto, Andrea Luciani, Rosaria Tamborini, Lucia Cullia, Gregorio De Micheli, Carlo Marinelli, Luciana Cosconati, Sandro Novellino, Ettore Lo Presti, Leonardo Cordeiro da Silva, Anabela Conti, Paola Hunter, William N. Costi, Maria P. Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity |
| title | Characterization
of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl
Ureido Based Inhibitors of Trypanosoma brucei FolD
and Testing for Antiparasitic Activity |
| title_full | Characterization
of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl
Ureido Based Inhibitors of Trypanosoma brucei FolD
and Testing for Antiparasitic Activity |
| title_fullStr | Characterization
of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl
Ureido Based Inhibitors of Trypanosoma brucei FolD
and Testing for Antiparasitic Activity |
| title_full_unstemmed | Characterization
of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl
Ureido Based Inhibitors of Trypanosoma brucei FolD
and Testing for Antiparasitic Activity |
| title_short | Characterization
of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl
Ureido Based Inhibitors of Trypanosoma brucei FolD
and Testing for Antiparasitic Activity |
| title_sort | characterization
of 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl
ureido based inhibitors of trypanosoma brucei fold
and testing for antiparasitic activity |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621507/ https://www.ncbi.nlm.nih.gov/pubmed/26322631 http://dx.doi.org/10.1021/acs.jmedchem.5b00687 |
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