Design, Synthesis and Biological Evaluation of 1-Fluoroalkyl-1,1-bisphosphonic Acids Against Trypanosoma cruzi AND Toxoplasma gondii.

SZAJNMAN, SERGIO H.; ROSSO, VALERIA; MALAYIL, L; GALIZZI, M; MORENO, SILVIA; DOCAMPO, ROBERTO; RODRIGUEZ, JUAN BAUTISTA

Sitges - Barcelona

Congreso; Twelfth Tetrahedron Symposium; 2011

Tetrahedron

Different enzymes involved in the biosynthesis of ergosterol and farnesyl diphosphate, and in protein prenylation, have been reported to be excellent targets against pathogenic parasites. For example, farnesyl pyrophosphate synthase (FPPS) has been demonstrated to be the target of bisphosphonates that have activity in vitro and in vivo against T. cruzi (the etiological agent of American trypanosomiasis or Chagas´ disease).1 Chemotherapy for Chagas´ disease still remains unsatisfactory due to limited efficacy and common side effects of the currently available drugs. The lack of vaccines and the impossibility of eradicating the vector bring about an urgent need of new antiparasitic agents, which are based on the metabolic differences between the host and the parasite. It is known that several bisphosphonates (BPs) are growth inhibitors of T. cruzi cells without toxicity for the host.1 Geminal phosphonates are pyrophosphate analogues in which a methylene group replaces the oxygen atom bridge between the two phosphorus atoms of the pyrophosphate moiety. The molecular target of bisphosphonates is FPPS. As BP-containing compounds are FDA-approved drugs for long-term treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control tropical diseases. Bearing in mind that representative BPs coordinate Mg+2 at the active site of TcFPPS in a tridentate manner, and the hydroxyl group at the C-1 position forms a hydrogen bond with an Asp250 residue, it was of interest the isosteric replacement of the -OH at C-1 by a fluorine atom.2 The title compounds were synthesized from tetraethyl ethenylidenbisphosphonate (2), was prepared from tetraethyl 1 (Scheme). The fluorine-containing BPs (7–16) were evaluated against T. cruzi (amastigotes) and the opportunistic parasite Toxoplasma gondii (tachyzoites) and their target enzymes TcFPPS and TgFPPS. Compound 15 resulted to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the very low nanomolar range