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

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• 作者：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 ; William N. Hunter ; Maria P. Costi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：7938-7948
• 全文大小：522K
• ISSN：1520-4804

文摘

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 渭M, against TbFolD and displayed antiparasitic activity against T. brucei (IC₅₀ 49 渭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.