Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy

  • J Med Chem. 2001 Mar 15;44(6):909-16. doi: 10.1021/jm0002578.
M B Martin  1 ,  J S Grimley ,  J C Lewis ,  H T Heath 3rd ,  B N Bailey ,  H Kendrick ,  V Yardley ,  A Caldera ,  R Lira ,  J A Urbina ,  S N Moreno ,  R Docampo ,  S L Croft ,  E Oldfield
Affiliations
  • 1. Departments of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
PMID: 11300872 DOI: 10.1021/jm0002578
Abstract

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.