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 ?M, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 ?M). 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 / T.C. Eadsforth, A. Pinto, R. Luciani, L. Tamborini, G. Cullia, C. De Micheli, L. Marinelli, S. Cosconati, E. Novellino, L. Lo Presti, A. Cordeiro da Silva, P. Conti, W.N. Hunter, M.P. Costi. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:20(2015 Oct 22), 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

A. Pinto
Secondo
;
L. Tamborini;G. Cullia;C. De Micheli;L. Lo Presti;P. Conti
;
2015-10-22

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 ?M, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 ?M). 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.
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/346374
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