Received for publication June 6, 2008.
Revised August 13, 2008.
Accepted for publication August 18, 2008.

The inhibitory effect of 2-halo derivatives of D-glucose on glycolysis and on the proliferation of the human malaria parasite Plasmodium falciparum

Abstract

The intraerythrocytic stage of the human malaria parasite Plasmodium falciparum relies on glycolysis for ATP generation, and since it has no energy stores a constant supply of glucose is necessary in order for the parasite to grow and multiply. The 2-substituted glucose analogues 2-deoxy-D-glucose (2-DG) and 2- fluoro-2-deoxy-D-glucose (2-FG) have previously been shown to inhibit the in vitro growth of P. falciparum and have been suggested to do so by inhibiting glycosylation in the parasite. In this study we have investigated the antiplasmodial mechanism of action of 2-DG and 2-FG and compared it to that of other 2-substituted-glucose analogues. The compounds tested inhibited parasite growth to varying degrees, with 2-FG being the most effective. The antiplasmodial activity of some, but not all, of the analogues could be altered by varying the glucose concentration in the culture medium; increasing the antiplasmodial activity of the analogues as the glucose concentration is reduced. A trend was observed between the antiplasmodial activity of these analogues and their ability to inhibit glucose accumulation, glucose phosphorylation by hexokinase and cytosolic pH regulation within the intraerythrocytic stage of the parasite. Our data are consistent with inhibition of glycolysis being a primary mechanism by which 2-DG and 2-FG inhibit parasite growth, and validate the early steps in glycolysis as viable drug targets.

Key words: ATP, antimalarials, glucose analogs, glycolysis, malaria, pH