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 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.
Martin
M B
MB
Departments of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Grimley
J S
JS
Lewis
J C
JC
Heath
H T
HT
Bailey
B N
BN
Kendrick
H
H
Yardley
V
V
Caldera
A
A
Lira
R
R
Urbina
J A
JA
Moreno
S N
SN
Docampo
R
R
Croft
S L
SL
Oldfield
E
E
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004164:Diphosphonates / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects; D014709:Vero Cells
D000981:Antiprotozoal Agents; D004164:Diphosphonates