title: Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis.
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 IC(50) values of 23microM and 26microM 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.
authors.affiliation: School of Chemistry, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Nowicki
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Tulloch
authors.forename: Liam
authors.initials: L
authors.lastname: Worralll
authors.forename: Iain W
authors.initials: IW
authors.lastname: McNae
authors.forename: Véronique
authors.initials: V
authors.lastname: Hannaert
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.forename: Linda A
authors.initials: LA
authors.lastname: Fothergill-Gilmore
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Turner
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006019:Glycolysis; D020128:Inhibitory Concentration 50; D007854:Lead / Q000737:chemistry*; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D025221:Phosphofructokinases / Q000037:antagonists & inhibitors; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D014344:Trypanocidal Agents; D007854:Lead; D025221:Phosphofructokinases; D011770:Pyruvate Kinase