Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucose-6-Phosphate Isomerase/antagonists & inhibitors , Glycerol Kinase/antagonists & inhibitors , Glycolysis/drug effects , Hexokinase/antagonists & inhibitors , Phosphoglycerate Kinase/antagonists & inhibitors , Trypanosoma brucei brucei/enzymology , Animals , Enzyme Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Several sets of compounds, active against different trypanosomes, Trypanosoma brucei and Trypanosoma cruzi are presented, the lethal doses for some of them being less than the micro-molar concentration. These compounds are designed by taking advantage of two metabolic features of these parasites, glucose metabolism and oxidative stress.
Subject(s)
Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/drug therapy , DNA, Protozoan/drug effects , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphate Aldolase/antagonists & inhibitors , Glucose/metabolism , Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists & inhibitors , Glycolysis/drug effects , Hexokinase/antagonists & inhibitors , Humans , Nifurtimox/pharmacology , Oxidative Stress/drug effects , Polyamines/metabolism , Trypanocidal Agents/administration & dosage , Trypanosoma brucei brucei/metabolism , Trypanosoma cruzi/metabolism , Trypanosomiasis, African/drug therapyABSTRACT
Glycolysis in the trypanosome represents an important target for the development of new therapeutic agents due to the fact that this metabolism is essential for the parasite, glucose being its sole source of energy. In addition, different features of this metabolism and those associated with glycolytic enzymes offer opportunities for the development of efficient and selective compounds. Examples are given in this work of inhibitors directed to the enzymes aldolase and glyceraldehyde-phosphate-dehydrogenase and also of molecules acting specifically on the clusters of basic amino-acids present at the surfaces of the glycolytic enzymes in the parasite.