Eadsforth Thomas C, Pinto Andrea, Luciani Rosaria, Tamborini Lucia, Cullia Gregorio, De Micheli Carlo, Marinelli Luciana, Cosconati Sandro, Novellino Ettore, Lo Presti Leonardo, Cordeiro da Silva Anabela, Conti Paola, Hunter William N, Costi Maria P
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
J Med Chem. 2015 Oct 22;58(20):7938-48. doi: 10.1021/acs.jmedchem.5b00687. Epub 2015 Sep 16.
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.
双功能酶N(5),N(10)-亚甲基四氢叶酸脱氢酶/环水解酶（FolD）对于锥虫科生物的生长至关重要。我们试图开发布氏锥虫FolD（TbFolD）的抑制剂作为潜在的抗寄生虫药物。合成了化合物2，并通过中间体化合物3的X射线晶体学明确确定了其分子结构。化合物2对TbFolD的IC50为2.2 μM，并对布氏锥虫显示出抗寄生虫活性（IC50为49 μM）。利用化合物2，我们获得了在存在NADP(+)和抑制剂的情况下TbFolD的首个X射线结构，这进而指导了一系列新型强效TbFolD抑制剂的合理设计。
