Bisphosphonates Inhibit the Growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum:  A Potential Route to Chemotherapy

We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone re...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-03, Vol.44 (6), p.909-916
Main Authors: MARTIN, Michael B., GRIMLEY, Joshua S., LEWIS, Jared C., HEATH, Huel T., BAILEY, Brian N., KENDRICK, Howard, YARDLEY, Vanessa, CALDERA, Aura, LIRA, Renee, URBINA, Julio A., MORENO, Silvia N. J., DOCAMPO, Roberto, CROFT, Simon L., OLDFIELD, Eric
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiparasitic agents
Antiprotozoal Agents - pharmacology
Biological and medical sciences
Cercopithecus aethiops
Diphosphonates - pharmacology
Leishmania donovani - drug effects
Medical sciences
Pharmacology. Drug treatments
Plasmodium falciparum - drug effects
Structure-Activity Relationship
Toxoplasma - drug effects
Trypanosoma brucei brucei - drug effects
Trypanosoma cruzi - drug effects
Vero Cells
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Summary:We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC(50) activity values against parasite replication (e.g. o-risedronate, IC(50) = 220 nM for T. brucei rhodesiense; risedronate, IC(50) = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0002578