The bifunctional enzyme N5,N10-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 IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 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.

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, T. C.; Pinto, A.; Luciani, R.; Tamborini, L.; Cullia, G.; De Micheli, C.; Marinelli, L.; Cosconati, S.; Novellino, E.; Lo Presti, L.; Cordeiro Da Silva, A.; Conti, P.; Hunter, W. N.; Costi, M. P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:20(2015), pp. 7938-7948. [10.1021/acs.jmedchem.5b00687]

Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity

Pinto A.;Luciani R.
Investigation
;
Marinelli L.;Costi M. P.
Funding Acquisition
2015-01-01

Abstract

The bifunctional enzyme N5,N10-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 IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 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.
58
20
7938
7948
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, T. C.; Pinto, A.; Luciani, R.; Tamborini, L.; Cullia, G.; De Micheli, C.; Marinelli, L.; Cosconati, S.; Novellino, E.; Lo Presti, L.; Cordeiro Da Silva, A.; Conti, P.; Hunter, W. N.; Costi, M. P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:20(2015), pp. 7938-7948. [10.1021/acs.jmedchem.5b00687]
Eadsforth, T. C.; Pinto, A.; Luciani, R.; Tamborini, L.; Cullia, G.; De Micheli, C.; Marinelli, L.; Cosconati, S.; Novellino, E.; Lo Presti, L.; Cordeiro Da Silva, A.; Conti, P.; Hunter, W. N.; Costi, M. P.
File in questo prodotto:
File Dimensione Formato  
FolD paper2015.pdf

non disponibili

Descrizione: Articolo principale
Tipologia: Versione pubblicata dall'editore
Dimensione 3.7 MB
Formato Adobe PDF
3.7 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1209233
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 10
social impact