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

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

  • J Med Chem. 2015 Oct 22;58(20):7938-48. doi: 10.1021/acs.jmedchem.5b00687.
Thomas C Eadsforth 1,  Andrea Pinto 2,  Rosaria Luciani 3,  Lucia Tamborini 2,  Gregorio Cullia 2,  Carlo De Micheli 2,  Luciana Marinelli 4,  Sandro Cosconati 5,  Ettore Novellino 4,  Leonardo Lo Presti 6,  Anabela Cordeiro da Silva 7,  Paola Conti 2,  William N Hunter 1,  Maria P Costi 3
Affiliations

Affiliations

  • 1 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
  • 2 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
  • 3 Department of Life Science, University of Modena and Reggio Emilia , Via Campi 103, 41125, Modena, Italy.
  • 4 Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , Via Montesano 49, 80131 Napoli, Italy.
  • 5 DiSTABiF, Seconda Università di Napoli , Via Vivaldi 43, 81100 Caserta, Italy.
  • 6 Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
  • 7 Instituto de Investigação e Inovação em Saúde, Instituto de Biologia Molecular e Cellular da Universidade do Porto, Departamento de Ciências Biológicas, Universidade do Porto , Porto, Portugal.
PMID: 26322631 DOI: 10.1021/acs.jmedchem.5b00687
Abstract

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 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.

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