RESUMO
Glucose metabolism is essential for survival of bloodstream form Trypanosoma brucei subspecies which cause human African trypanosomiasis (sleeping sickness). Hexose analogues may represent good compounds to inhibit glucose metabolism in these cells. Delivery of such compounds to the parasite is a major consideration in drug development. A series of D-glucose and D-fructose analogues were developed to explore the limits of the structure-activity relationship of the THT1 hexose transporter of bloodstream form African trypanosomes, a portal that might be exploited for drug uptake. D-glucose analogues with substituents at the C2 and C6 position continued to interact with the exofacial hexose binding site of the transporter. There was a limit to the size at C6 which still permitted recognition, although compounds carrying large groups at position C2 were still recognised. However, radiolabelled N-acetyl-D-[1-14C] glucosamine was not internalised by trypanosomes, in spite of the ability of this compound to inhibit glucose uptake, indicating that there is a limit to the size of C2 substituent that allows translocation. Addition of an alkylating group (bromoacetyl) at position C2 in the D-glucose series and at position 6 in the D-fructose set, created two analogues which interact with the transporter and kill trypanosomes in vitro. This indicates that inhibition of the transporter may be a good means of killing trypanosomes.
