## 8 Potential Inhibitors of Farnesyl Diphosphate Synthase  
An enzyme that belongs to the (E)-prenyltransferases, i.e., farnesyl diphosphate synthase (FPPS), catalyzes the production of farnesyl pyrophosphate (FPP; a C15 product) through the condensation of two units of isopentenyl diphosphate (IPP, C5) along with one unit of dimethylallyl diphosphate (DMAPP, C5) [65]. According to the literature, a variety of compounds (Figures 8 and 9) have been reported to inhibit the activity of farnesyl diphosphate synthase, an enzyme involved in several metabolic pathways, including sterol biosynthesis. _Trypanosoma_ are parasite species that are responsible for leishmaniasis and trypanosomiasis in humans and strongly depend on metabolites, such as ergosterol and other proteins, for their growth and survival. It is therefore hypothesized that farnesyl diphosphate synthase is among the attractive targets for the discovery of anti-_Trypanosoma_ hit compounds. In a previous study by [PERSON] et al. [66], _Trypanosoma cruzi_ farnesyl pyrophosphate synthase was used as an experimental model to assess the inhibitory potential of a series of nonnitrogen-containing bisphosphonates, including compounds **(41-50)** (IC\({}_{50}\): 42.83, 1.94, 2.37, 9.36, 8.45, 5.71, 5.67, 4.54, 19.73, and 4.25 uM, respectively). Figure 8: Prospective inhibitors of farnesyl pyrophosphate synthase (compounds (**41–61**)). Figure 9: Chemical structures of potent inhibitors of farnesyl diphosphate synthase (**62**–**74**). Upon incubation of compounds (**41**, **43**, **45**, and **49**) with the amastigote forms of _Trypanosoma cruzi_, the inhibition was effective, yielding IC\({}_{50}\) values of 21.4, 18.1, 65.8, and 22.36 uM, respectively. Against _Trypanosoma brucei_ farnesyl pyrophosphate synthase, compounds (**41**-**45**) afforded IC\({}_{50}\) values of 3.12, 0.66, 3.57, and 4.54 uM, respectively [66]. Nonnitrogen-containing BPs are known to induce apoptosis, as these compounds metabolize into cytotoxic, nonhydrolyzable analogs of ATP, which interfere with mitochondrial function [67, 68, 69, 70]. Other nitrogen-containing BPs (compounds (**51**-**60**)) were also reported as inhibitors of farnesyl pyrophosphate synthase. Complete growth arrest of the extracellular epimastigote form of _T. cruzi_ (IC\({}_{50}\): 150 uM) by the bisphosphonate risedronate (**51**) was attributed to the depletion of the parasite's endogenous sterols (inhibition of ergosterol synthesis with an IC\({}_{50}\) value of 65.4 uM) [71]. Likewise, two alkyl 1-amino-1,1-bisphosphonates (compounds (**52** and **53**)) inhibited _T. cruzi_ farnesyl pyrophosphate synthase with IC\({}_{50}\) values of 0.382 and 3.57 uM, respectively. Further in vitro screening of compounds (**52** and **53**) against the amastigote forms of _T. cruzi_ showed inhibitory effects with IC\({}_{50}\) values of 77.0 and 72.0 uM, respectively [72]. [PERSON] et al. [73] described the inhibitory effect of a series of 2-alkylaminoethyl-1,1-bisphosphonate acids (compounds (**54**-**60**)) [1-[(n-But-1-ylamino)ethyl] 1,1-bisphosphonic acid (**29**); 1-[(n-Pent-1-ylamino)ethyl] 1,1-bisphosphonic acid (**30**); 1-[(n-Hex-1-ylamino)ethyl] 1,1-bisphosphonic acid (**31**); 1-[(n-Hep-1-ylamino)ethyl] 1,1-bisphosphonic acid (**32**); 1-[(n-Oct-1-ylamino)ethyl] 1,1-bisphosphonic acid (**54**); 1-[(3-Methyl-but-1-ylamino)ethyl] 1,1-bisphosphonic acid (**33**); and 1-[(tert-Butylamino)ethyl] 1,1-bisphosphonic acid (**55**) against the intracellular form of _T. cruzi_, exhibiting IC\({}_{50}\) values of 2.28, 1.84, 0.49, 0.058, 1.014, 0.42 and 1.21 uM, for compounds (**29**-**32**, **54**, **33**, and **55**), respectively. These compounds were further assayed for inhibitory activity on _T. cruzi_ farnesyl diphosphate synthase, and the results showed IC\({}_{50}\) values of 2.28, 1.84, 0.49, 0.058, 1.014, 0.42, and 1.21 uM for compounds (**29**-**32**, **54**, **33**, and **55**), respectively [73].