Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis
- 作者：Matthew W. Nowicki ; Lindsay B. Tulloch ; Liam Worralll ; Iain W. McNae ; Vé ; ronique Hannaert ; Paul A.M. Michels ; Linda A. Fothergill-Gilmore ; Malcolm D. Walkinshaw ; Nicholas J. Turner
- 关键词：Pyruvate kinase ; Phosphofructokinase ; Inhibitors ; Leishmania ; Trypanosome ; Parasite ; Drug development ; Glycolysis
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2008
- 期刊代码：9_09680896
- 类别：ch
- 出版时间：1 May 2008
- 卷：16
- 期：9
- 页码：5050-5061
- 文件大小：679 K
摘要
The glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of Trypanosoma and Leishmania. We report the design and the synthesis of inhibitors targeted against Trypanosoma brucei phosphofructokinase (PFK) and Leishmania mexicana pyruvate kinase (PyK). Stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with IC50 values of 23 μM and 26 μM against PFK and PyK, respectively. Trypanocidal activity also showed potency in the low micromolar range and confirms these inhibitors as promising candidates for the development towards the design of anti-trypanosomal drugs.