Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

Thomas C. Eadsforth, Andrea Pinto, Rosaria Luciani, Lucia Tamborini, Gregorio Cullia, Carlo De Micheli, Luciana Marinelli, Sandro Cosconati, Ettore Novellino, Leonardo Lo Presti, Anabela Cordeiro Da Silva, Paola Conti (Lead / Corresponding author), William N. Hunter (Lead / Corresponding author), Maria P. Costi (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7938-7948
Number of pages11
JournalJournal of Medicinal Chemistry
Volume58
Issue number20
Early online date31 Aug 2015
DOIs
Publication statusPublished - 22 Oct 2015

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