Bisphosphonates Inhibit the Growth ofTrypanosomabrucei,Trypanosomacruzi,Leishmaniadonovani,Toxoplasmagondii, andPlasmodiumfalciparum:  A Potential Route to Chemotherapy

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.

The Farnesyl-diphosphate/Geranylgeranyl-diphosphate Synthase of Toxoplasma gondii Is a Bifunctional Enzyme and a Molecular Target of Bisphosphonates

“…Bisphosphonates-The structures of the bisphosphonates investigated are as shown in Scheme 1, and their synthesis followed standard methods (15).…”

“…This pattern of activity may at first appear surprising because the compound is an n-alkyl bisphosphonate lacking the key positively charged nitrogen site present in the potent bone resorption drugs (such as risedronate, 2) which inhibit human FPPS, and there is only low activity of this compound against an L. major FPPS and in human ␥␦ T cell activation (which involves FPPS inhibition) (Table 3). However, the long alkyl chain bisphosphonates are actually among the most potent inhibitors of human GGPPS (29) (Table 3) in addition to being among the more active inhibitors of P. falciparum cell growth (15), correlating perhaps with the presence of the serine/phenylalanine sequence upstream of the FARM region (which is cysteine/phenylalanine in TgFPPS, Fig. 8).…”

“…In early work, it was shown that nitrogen-containing bisphosphonates were effective in the inhibition of T. cruzi, in vitro and in vivo, without toxicity to the host cell (14). More recently, we tested a series of bisphosphonates for their effects on the growth of T. gondii, T. brucei rhodesiense, Leishmania donovani, and Plasmodium falciparum in vitro, finding that several bisphosphonates can effectively inhibit the growth of these parasites (15). Moreover, in vivo testing of bisphosphonates against T. gondii in mice has shown that one of the nitrogen-containing bisphosphonates, risedronate, significantly increases the survival of mice infected by T. gondii (16).…”

Trypanocidal activity, cytotoxicity and histone modifications induced by malformin A1 isolated from the marine-derived fungus Aspergillus tubingensis IFM 63452

“…Protozoan diseases are considered to be among the world's most widespread human health problems, with the greatest morbidity attributed to trypanosomatid and apicomplexan parasite infections (Martin et al 2001). However, studies on the mode of action of commercially available antiprotozoal drugs have linked their antiparasitic activity with mammalian host intoxication (Urbina 2002).…”

Facile Synthesis of Bisphosphonates

“…[10] Some others possess anti-inflammatory properties and may be effective in the treatment of rheumatoid arthritis [11] or exhibit anti-parasitic activity. [12] In the recent years, PEG, a biologically acceptable polymer used extensively in drug delivery and in bioconjugates as tool for diagnostics, emerged as a powerful phase transfer catalyst and performs many useful organic transformations under mild reaction conditions. Moreover, PEG and its monomethyl ethers are inexpensive, thermally stable, recoverable, and are proved to be non-toxic phase-transfer catalysts.…”