Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Abstract

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 μM, while this compound showed an IC 50 value of 0.49 μM 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 μM and 2.6 μM, respectively. In this case, 19 inhibited in at least two different enzymes of T. cruzi (TcFPPS and solanesyl diphosphate synthase (TcSPPS); 1.01 μM and 0.25 μM, 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.

Solanesyl Diphosphate Synthase, an Enzyme of the Ubiquinone Synthetic Pathway, Is Required throughout the Life Cycle of Trypanosoma brucei

“…These effects were mimicked in the wild-type cells by the TbSPPS bisphosphonate inhibitor 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid (compound 1) (9). In vivo, infected mice displayed longer survival when TbSPPS was ablated by RNA interferenec (RNAi), confirming its importance in the metabolism of the parasite.…”

“…Activities of two key enzymes of this pathway in T. brucei, namely, farnesyl diphosphate synthase and farnesyl transferase, have been characterized (5,6,7). Moreover, promising inhibitors of farnesyl diphosphate synthase with antiparasitic activities have been tested in vitro (8,9,10) and in vivo (11).…”

“…On the other hand, enzymes synthesizing longer isoprenoid chains have so far not been thoroughly studied in trypanosomatids (9,12). Their product is likely to be incorporated into ubiquinone (UQ), which has a central role in respiration of T. brucei and has two well-studied metabolically distinct stages in its life cycle.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…As an electron-deficient alkene, it can undergo conjugate addition of strong and mild nucleophiles, with amines belonging to the latter class. Primary amines undergo smooth Michael addition (Scheme 18), however, the obtained compounds 33 must be quickly purified and hydrolyzed since they tend to undergo a retro-Michael reaction [103,104]. Fortunately, free acids 34 are substantially more stable.…”

“…(EtO) 2 The reactivity of vinylidenebisphosphonates has been used for the synthesis of derivatives of various analogues of fluoroquinolone antibacterial agents [105,106], heteroaromatics with potential pharmaceutical applications [107,108], simple antiplasmodial agents [103,104], HIV reverse transcriptase inhibitors [59,93], potential anti-osteoporotic agents [109,110], and N-alkylated antitumor pyridines [111]. Some representatives of these compounds (35)(36)(37)(38)(39) are shown in Scheme 19.…”