## 8 Potential Inhibitors of Farnesyl Diphosphate Synthase
Additionally, 1-[(n-dodec-1-ylamino)ethyl] 1,1-bisphosphonic acid (**56**) inhibited the growth of a more clinically relevant form of _Trypanosoma cruzi_ with an IC\({}_{50}\) value of 0.67 uM compared with benzmidazole, the positive control considered (IC\({}_{50}\): 2.77 uM). This compound was also effective against amastigote forms of _T. cruzi_, exhibiting an IC\({}_{50}\) value of 0.67 uM. The target enzyme _T. cruzi_ farnesyl diphosphate synthase (TcFPPS) was also inhibited by this compound (IC\({}_{50}\) value: 0.81 uM) [74]. Furthermore, [PERSON] et al. [9] synthesized a series of 2-alkyl aminoethyl-1,1-bisphosphonate acids (compounds (**29**-**32**, **55**, **57**, and **34**)) as potent inhibitors of _T. cruzi_ farnesyl pyrophosphate synthase with IC\({}_{50}\) values of 2.28, 1.84, 0.49, 0.058, 1.21, 69.8, and 57.3 nM, respectively. Further in vitro studies demonstrated that compounds (**29**-**32**, **55**, **57**, and **34**) inhibit the growth of _T. cruzi_ amastigotes with IC\({}_{50}\) values of 4.8, 0.54, 0.84, 10.0, 10.0, 1.39, and \(>\)10 nM, respectively [9]. Additionally, 2-(n-propylamino) ethane-1,1-diyl]bisphosphonic acid (**58**) and [2-(n-heptylamino)ethane-1,1-diyl]bisphosphonic acid (**32**) afforded IC\({}_{50}\) values of 38.0 and 58.0 nM, respectively, when tested on _T. cruzi_ farnesyl diphosphate synthase [75]. In a paper published by [PERSON] et al. [76], compounds (**59**-**61**) exhibited ED\({}_{50}\) values of 15.8, 12.8, and 22.4 uM, respectively, when tested against amastigotes of _T. cruzi_. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) with IC\({}_{50}\) values of 6.4, 1.7, and 0.097 uM, respectively [76]. Moreover, [PERSON] et al. [77] described the inhibitory effect of a series of compounds (**62**-**71**) on farnesyl diphosphate synthase with IC\({}_{50}\) values of 1.8, 1.9, 2.5, 7.0, 10.7, 13.7, 20.3, 21.0, 22.3, and 35.0 uM for compounds (**62**-**71**), respectively [77]. In a paper published by [PERSON] et al. [12], the quinone methide celastrol (**72**) showed an inhibitory effect on _Trypanosoma brucei_ farnesyl diphosphate synthase (FPPS) with an IC\({}_{50}\) value \(\sim\)20 uM [12]. In 2014, [PERSON] et al. [78] reported the inhibitory potential of two nitrogen-containing bisphosphonates [1-(2-hydroxy-2,2-diphosphonoethyl)-3-phenylpyridinium (**73**) and 3-fluoro-1-(2-hydroxy-2,2-diphosphonoethyl)-pyridinium (**74**) in inhibiting _L. major_ farnesyl diphosphate synthase with Ki values of 9 and 50 uM, respectively, vs. zoledronate (11 uM) [78]. Recently, [PERSON] et al. [79] reported the inhibitory effect of three 1-alkylaminomethyl-1,1-bisphosphonate acids (compounds (**31**, **32**, and **56**)), with IC\({}_{50}\) values of 0.49, 0.058, and 0.81 \(\upmu\)M, respectively, against _Trypanosoma brucei_ farnesyl pyrophosphate synthase. After incubation of compounds 31, 32, and 56 with _T. cruzi_, IC\({}_{50}\) values of 0.84, 10.0, and 0.67 \(\upmu\)M were obtained, respectively, vs. benznidazole (IC\({}_{50}\): 2.58 \(\upmu\)M) [79]. As already discussed, farnesyl diphosphate synthase is one of the crucial enzymes involved in the isoprenoid pathway, which is required for sterol biosynthesis. In the present study, forty (40) inhibitors of farnesyl diphosphate synthase were recorded across the literature. Among these compounds, nineteen (19) were reported to be active against _Trypanosoma cruzi_ and included compounds (**41**, **43**, **45** and **49**) (IC\({}_{50}\) values: 21.4, 18.1, 65.8 and 22.36 \(\upmu\)M, respectively; amastigotes forms of _T. cruzi_, [66]); compounds (**52** and **53**) (IC\({}_{50}\) values of 77.0 and 72.0 \(\upmu\)M, respectively, [72]; compounds (**29**-**32**, **54**, **33**, and **55**), IC\({}_{50}\) values: 2.28, 1.84, 0.49, 0.058, 1.014, 0.42 and 1.21 \(\upmu\)M, respectively, [73]; 1-[(n-dodec-1-ylamino)ethyl] 1,1-bisphosphonate acid (56); IC\({}_{50}\): 0.67 \(\upmu\)M; clinically relevant form of _T.