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Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis |
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| Authors: | Nowicki Matthew W Tulloch Lindsay B Worralll Liam McNae Iain W Hannaert Véronique Michels Paul A M Fothergill-Gilmore Linda A Walkinshaw Malcolm D Turner Nicholas J |
| Institution: | aSchool of Chemistry, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK bStructural Biochemistry Group, Institute of Structural and Molecular Biology, University of Edinburgh, King’s Buildings, Mayfield Road, Edinburgh EH9 3JR, UK cResearch Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Université Catholique de Louvain (UCL), Avenue Hippocrate 74, B-1200 Brussels, Belgium |
| Abstract: | 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. |
| Keywords: | Pyruvate kinase Phosphofructokinase Inhibitors Leishmania Trypanosome Parasite Drug development Glycolysis |
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