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.
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.
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
authors: Thomas C
authors: TC
authors: Eadsforth
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors: Andrea
authors: A
authors: Pinto
authors: Department of Life Science, University of Modena and Reggio Emilia , Via Campi 103, 41125, Modena, Italy.
authors: Rosaria
authors: R
authors: Luciani
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors: Lucia
authors: L
authors: Tamborini
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors: Gregorio
authors: G
authors: Cullia
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors: Carlo
authors: C
authors: De Micheli
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , Via Montesano 49, 80131 Napoli, Italy.
authors: Luciana
authors: L
authors: Marinelli
authors: DiSTABiF, Seconda Università di Napoli , Via Vivaldi 43, 81100 Caserta, Italy.
authors: Sandro
authors: S
authors: Cosconati
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , Via Montesano 49, 80131 Napoli, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors: Leonardo
authors: L
authors: Lo Presti
authors: 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.
authors: Anabela
authors: A
authors: Cordeiro da Silva
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors: Paola
authors: P
authors: Conti
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
authors: William N
authors: WN
authors: Hunter
authors: Department of Life Science, University of Modena and Reggio Emilia , Via Campi 103, 41125, Modena, Italy.
authors: Maria P
authors: MP
authors: Costi
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D011744:Pyrimidinones; D014344:Trypanocidal Agents; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)