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

Naughton, J. A., Hughes, Ruth, Bray, Patrick and Bell, A. (2008) 'Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum'. Biochemical Pharmacology, Vol 75, Issue 8, pp. 1580-1587.

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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 phosphorothicamidates (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 [C-14]trifluralin in comparison with [H-3]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 similar to 300 times the external concentration and vinblastine at up to similar to 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. (c) 2008 Elsevier Inc. All rights reserved.

Item Type: Article
Uncontrolled Keywords: malaria t trifluralin vinblastine accumulation microtubules antitubulin herbicide trifluralin dolastatin-10 malaria dinitroaniline erythrocytes resistance binding retention tubulin cells
Subjects: WB Practice of Medicine > Therapeutics > WB 330 Drug therapy
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
QV Pharmacology > QV 38 Drug action.
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):
Depositing User: Mary Creegan
Date Deposited: 19 Jul 2010 10:28
Last Modified: 17 Jul 2020 10:56


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