The effect of a series of 2-alkylaminoethyl-1,1-bisphosphonic
acids against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of
American trypanosomiasis (
Chagas' disease), and against tachyzoites of Toxoplasma gondii has been studied. Most of these drugs exhibited an extremely potent inhibitory action against the intracellular form of T. cruzi, exhibiting IC(50) values at the low micromolar level. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi
farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for
Chagas' disease chemotherapy.
Compound 17 was an effective agent against amastigotes exhibiting an IC(50) value of 0.84 microM, while this compound showed an IC(50) value of 0.49 microM against the target
enzyme TcFPPS. Interestingly, compound 19 was very effective against both T. cruzi and T. gondii exhibiting IC(50) values of 4.1 microM and 2.6 microM, respectively. In this case, 19 inhibited at least two different
enzymes of T. cruzi (TcFPPS and
solanesyl diphosphate synthase (TcSPPS); 1.01 microM and 0.25 microM, respectively), while it inhibited TgFPPS in T. gondii. In general, this family of drugs was less effective against the activity of T. cruzi
SPPS and against T. gondii growth in vitro. As
bisphosphonate-containing compounds are FDA-approved drugs for the treatment of
bone resorption disorders, their potential low toxicity makes them good candidates to control tropical diseases.