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  • In Apicomplexan parasites such as Toxoplasma gondii isopreno

    2022-01-18

    In Apicomplexan parasites such as Toxoplasma gondii isoprenoids are biosynthesized through the DOXP/MEP pathway as illustrated in Scheme 2. In addition, T. gondii possesses a bifunctional FPPS/GGPPS (TgFPPS) that is able to catalyze the formation of both FPP and GGPP.5, 6 The FPPS gene appears to be essential in all organisms.7, 8 Comparison of the amino 9292 sequence of FPPSs from different organisms (bacteria to higher eukaryotes) shows the presence of seven conserved regions including two aspartate-rich domains that are very important for the catalytic action and most likely act as the binding sites for IPP and the allylic substrates. All the FPPSs that have been characterized are homodimeric enzymes, and require divalent cations such as Mg2+ or Mn2+ for activity. On the other hand, bisphosphonates (2) are pyrophosphate (1) analogues in which a methylene group replaces the oxygen atom bridge between the two phosphorus atoms of the pyrophosphate moiety. The substitution of carbon with different side chains has generated a large family of compounds. Several bisphosphonates are potent inhibitors of bone resorption and are in clinical use for the treatment of different bone disorders. Acidocalcisomes are equivalent in composition to the bone mineral; the accumulation of bisphosphonates in these organelles, as they do in bone mineral, facilitates their antiparasitic action. Aminobisphosphonates such as pamidronate (3), alendronate (4), and risedronate (5), were first found to be effective in the inhibition of T. cruzi in vitro and in vivo without toxicity to the host cells (Fig. 1). In addition, some bisphosphonates were growth inhibitors of T. gondii, T. brucei rhodesiense, Leishmania donovani and Plasmodium falciparum.13, 14, 15, 16 In vivo testing in mice has shown that risedronate can significantly increase the survival of mice infected by T. cruzi.17, 18 All these results indicate that bisphosphonates are promising candidate drugs to treat infections by T. cruzi and other pathogenic parasites. In fact, they have already been developed to treat other diseases and consequently have low toxicity; their structures are simple and easy to synthesize; these compounds have shown effective inhibitory activity against T. cruzi in vitro and in vivo.17, 18 Of particular interest are linear bisphosphonates, specifically, 2-alkyl(amino)ethyl derivatives, which can be considered as promising antiparasitic agents.19, 20 These bisphosphonate derivatives exhibit potent cellular activity against intracellular T. cruzi, which is one of the clinically relevant forms of this parasite, having IC50 values at the low nanomolar level against the target enzyme (TcFPPS).19, 20 In addition, at the present time, linear 1-hydroxy-, 1-alkyl-, and 1-amino-1,1-bisphosphonates such as 6–9 can be considered as useful structures to establish rigorous SAR studies as antiparasitic agent targeting TcFPPS.5, 21, 22, 23, 24 In fact, these compounds show a broad range of antiparasitic activity against trypanosomatids and Apicompexan. For example, 6 is a potent growth inhibitor of T. cruzi (amastigotes) and also against T. gondii (tachyzoites),5, 24 whereas 7 is effective against P. falciparum. Besides, α-fluoro-1,1-bisphosphonates of formula 10 and 11 are devoid of cellular activity against T. cruzi or TcFPPS, but they are extremely potent inhibitors of the enzymatic activity of T. gondii FPPS exhibiting IC50 values of 35nM and 60nM, respectively. The high selectivity observed by these fluorine-containing bisphosphonates against TgFPPS versus TcFPPS can be rationalized by the evidence that the amino acid sequences of these enzymes have less than 50% identity. (Fig. 2). As mentioned before, 12–14 are promising anti-T. cruzi agents. For example, 12 exhibit an ED50 value of 0.84μM against T. cruzi (amastigotes), which is fifteen times more potent than the well-known antiparasitic agent WC-9 under the same assays conditions. In addition, 13 is an extremely potent inhibitor of the enzymatic activity of TcFPPS (IC50=0.058μM) and of TgFPPS (IC50=0.095μM), whereas the long chain length derivative 14 is an effective growth inhibitors of intracellular T. cruzi proliferation (ED50=0.67μM) compared to benznidazole (ED50=2.77μM). Sulfur-containing bisphosphonates also presents good prospective as putative lead drugs. For example, 15 and 16 are potent anti-Toxoplasma agents and, to a lesser extent, efficient anti-T. cruzi agents. For example, 15 has a potent cellular activity against tachyzoites of T. gondii (ED50=1.8μM), which was associated with a potent inhibition of the enzymatic activity of TgFPPS (IC50=0.021μM). Compound 15 is also effective towards TcFPPS (IC50=0.097μM). Moreover, 16 exhibits an extremely potent inhibitory action against TgFPPS with an IC50 value as low as 0.009μM (Fig. 2). It is worth mentioning that similar activity have also been reported for some lipophilic bisphosphonates, including 2-alkylaminoethyl compounds lacking the hydroxyl group at C-1, against another Apicomplexan parasite, P. falciparum.28, 29