Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic

ROSSO, VALERIA SOLEDAD; SZAJNMAN, SERGIO HERNÁN; MALAYIL, LEENA; GALLIZI, MELINA; MORENO, SILVIA N.; DOCAMPO, ROBERTO; RODRIGUEZ, JUAN BAUTISTA

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND ; Año: 2011 vol. 19 p. 2211 - 2217

0968-0896

The effect of long chain 2-alkylaminoethyl-1,1-bisphosphonates 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 was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC50 values at the nanomolar range. 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 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC50 value of 0.67 mM, while this compound showed an IC50 value of 0.81 mM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC50 value of 3.2 mM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC50 values of 6.23 mM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC50 = 0.29 mM) 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 different tropical diseases.