Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 9; pp. 5050 - 5061
• Main 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.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2008; Elsevier Science
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Design; Drug development; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycolysis; Inhibitors; Inhibitory Concentration 50; Lead - chemistry; Leishmania; Leishmania mexicana; Leishmania mexicana - drug effects; Leishmania mexicana - enzymology; Leishmania mexicana - metabolism; Medical sciences; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Parasite; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Phosphofructokinase; Phosphofructokinases - antagonists & inhibitors; Pyruvate kinase; Pyruvate Kinase - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology; Trypanosoma brucei brucei - metabolism; Trypanosome; Inhibitors; Pyruvate kinase; Leishmania; Parasite; Glycolysis; Drug development; Phosphofructokinase; Trypanosome; Kinetoplastida; Drug; Protozoa; Trypanosoma; Enzyme; Parasite; Drug development; Glycolysis; Transferases; In vitro; Biological activity; Research and development; Antiprotozoal agent; Chemical compound library; Chlorine Organic compounds; Uronic acid; Parasiticide; Inhibitor; Chemical synthesis; Pyruvate kinase; Phosphofructokinase; Inhibitors; Leishmania; Trypanosome
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.03.045

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 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.