## 10 Authors' Opinion on the Topic  
Neglected tropical diseases, such as leishmaniasises and trypanosomiasises, are prevalent in several sub-Saharan African and South American countries [2]. These diseases are caused by trypanosomatid parasites that interact with a wide range of insects and mammals to complete their life cycles. In general, _Trypanosoma_ and _Leishmania_ species are the parasites causing trypanosomiasises and leishmaniasises, respectively. A number of approaches, including phenotypic drug discovery and target-based drug discovery, have been used to identify anti-_Trypanosomatidae_ compounds. We have summarized and discussed inhibitors of squalene synthase and farnesyl diphosphate synthase in this manuscript. Notably, a number of inhibitors of these enzymes exhibited moderate to high anti-trypanosomatid activity upon in vitro phenotypic screening, attesting to the involvement of squalene synthase and farnesyl diphosphate synthase in the pathogenesis of trypanosomatids. Indeed, squalene synthase and farnesyl diphosphate synthase are the main enzymes that intervene in the isoprenoid pathway and the biosynthesis of ergosterol and other sterol compounds in trypanosomatids. The five best inhibitors of squalene synthase that displayed superior anti-trypanosomatid activity included compounds (30, 31, and 33) (IC\({}_{50}\) values: 0.54, 0.84, and 0.94 nM, respectively; [9]) and compounds (22 and 23) (IC\({}_{508}\): 1.7 and 14.7 nM, respectively; [59]). The five best inhibitors of farnesyl diphosphate synthase that exhibited higher anti-trypanosomatid activity included compound (56); IC\({}_{50}\): 0.67 uM [74]; (30 and  
**31**) (IC\({}_{50}\)s: 0.54 and 0.84 nM, respectively [9]; and (**31** and **56**) (IC\({}_{50}\)s: 0.84 and 0.67 \(\upmu\)M, respectively) [79]. More importantly, three compounds that showed anti-_T Trypanosomatidae_ activity were identified as inhibitors of both farnesyl diphosphate synthase and squalene synthase and included compounds (**30**, **31**, and **33**). Based on these observations, squalene synthase and farnesyl diphosphate synthase are potential targets for the identification of hit compounds that can serve as scaffolds for the discovery of anti-T Trypanosomatid drugs. However, more studies are needed to potentially verify this target-based drug discovery against traditional phenotypic drug screening, as almost half of the reported squalene synthase and farnesyl diphosphate synthase inhibitors have not been tested on trypanosomatids. Thus, doors are opened for researchers who work on anti-trypanosomatid drug discovery to screen such inhibitors. More in vitro and in vivo toxicity studies, pharmacokinetics, and structural medications of the most prominent scaffolds are desired to improve and select the best potential hit candidates that can be pursued further for anti-trypanosomatid drug discovery. Although several strategies have been established for anti-_Trypanosomatidae_ drug discovery, (i) testing for inhibitors against disease-relevant targets, (ii) screening for growth inhibitors against the whole parasite through in vitro cell culturing, and (iii) searching for anti-trypanosomatid therapies among previously known drugs (repositioning of known molecules) are mainly employed to identify hit compounds that can serve as scaffolds for the development of new agents against trypanosomiasis and leishmanasis [81, 82].