Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum.

Malaria is a disease in desperate need of new chemotherapeutic approaches. Certain microtubule inhibitors, including vinblastine and taxol, have highly potent activity against malarial parasites and disrupt the normal microtubular structures of intra-erythrocytic parasites at relevant concentrations. While these inhibitors are useful tools, their potential as anti-malarial drugs is limited by their high toxicity to mammalian cells. In contrast, two classes of antimitotic herbicide, namely dinitroanilines (e.g. trifluralin and oryzalin) and phosphorothioamidates (e.g. amiprophosmethyl), exhibit moderate activity against the major human malarial parasite Plasmodium falciparum in culture but very low mammalian cytotoxicity. We examined the dynamics and kinetics of uptake and subcellular compartmentation of [14C]trifluralin in comparison with [3H]vinblastine. We wished to determine whether the relatively modest activity of trifluralin was the consequence of poor uptake into parasite cells. Trifluralin accumulated in parasite-infected erythrocytes to approximately 300 times the external concentration and vinblastine at up to approximately 110 times. Accumulation into uninfected erythrocytes was much lower. Uptake of trifluralin was rapid, non-saturable and readily reversed. It appears that the hydrophobic nature of trifluralin leads to accumulation largely in the membranes of the parasite, reducing the levels in the soluble fraction and limiting access to its microtubular target. By contrast, vinblastine accumulated predominantly in the soluble fraction and uptake was saturable and mostly irreversible, consistent with binding predominantly to tubulin. The results indicate that synthesis of more polar trifluralin derivatives may be a promising approach to designing microtubule inhibitors with more potent antimalarial activity.