## 7 Potential Inhibitors of Squalene Synthas
This research group also found that (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride (20) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride (21) inhibit squalene synthase derived from human hepatoma cells, with IC\({}_{50}\) values of 160 and 79 nM, respectively [55]. In 2004, [PERSON] et al. [11] prepared two other quinuclidine-based derivatives [(3R)-3-[[2-benzyl-6-(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl)pyridin-3-yl]ethylinyl]quinuclidin-3-ol monohydrate (22) and ({3R})-3-[[2-benzyl-6-(3-methoxypropyl)pyridin-3-yl]ethylinyl]quinuclidin-3-ol) (23)], which exhibited noncompetitive inhibition toward _T. cruzi_ proteins with IC\({}_{50}\) values of 5.4 and 7.2 nM, respectively, for glycosomal squalene synthase and 15 and 5.5 nM, respectively, for microsomal squalene synthase of _T. cruzi_ epimastigotes. To verify the direct effect on the parasite in culture, further screening of compounds (22) and (23) afforded IC\({}_{50}\) values of 10 nM and 0.4 to 1.6 nM against extracellular epimastigotes and intracellular amastigotes, respectively. Under in vivo conditions, 22 was able to provide full protection against death and completely arrest the development of parasitemia when given at a dose of 50 mg/kg of body weight for 30 days [11,56]. Other biphenyl quinuclidine derivatives (24-26) were also evaluated for their inhibitory activity toward _L. major_ squalene synthase. Compounds (3-(biphenyl-4-yl)-3-hydroxyquinuclidine) (24), (3-(biphenyl-4-yl)-2,3-dehydro-quinuclidine)(**25**), and (3-(biphenyl-4-yl-40-hydroxy)-2,3-dehydro-quinuclidine) (**26**) afforded IC\({}_{50}\) values of 0.013, 0.243, and 0.096 uM, respectively. Against _L. danovani_ intracellular amastigotes, compounds (**24-26**) afforded ED\({}_{50}\) values of 29.0, 74.3 and \(>\)108 uM, respectively, attesting to the enzymatic effectiveness of these compounds against _L. major_ squalene synthase [57]. In 2006, [PERSON] et al. [58] reported the inhibitory potential of two biphenyl derivatives, i.e., 2-(4-Biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide (**27**) and 2-(4-biphenyl)-2-(3-nitrooxy propoxy)-4-methylmorpholine, hydrobromide (**28**) on squalene synthase in rabbit liver microsomes with IC\({}_{50}\) values of 33 and 0.6 uM, respectively. In human liver microsomes, compounds (**27** and **28**) afforded IC\({}_{50}\) values of 63 and 1 uM, respectively. Simvastatin (a standard squalene synthase inhibitor; IC\({}_{50}\): 30 uM) inhibits the activity of the rabbit enzyme by 23% but had poor or no effect on the activity of the human enzyme (percent inhibition: 19% at 100 uM) [58]. Developed as cholesterol-lowering agents, two arylquinuclidine derivatives ({3R})-3-[[2-benzyl-6-(3-methoxypropyl)-pyridin-3-yl]ethylvinyl]quinuclidin-3-ol (ER-119884) (**23**) and ({3R})-3-[[2-benzyl-6-[3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridin-3-yl]quinuclidin-3-ol monohydrate (**22**) were found to be potent noncompetitive inhibitors of native _L. amazonensis_ squalene synthase (glycosomal SQS: Ki = 6.4 and 6.9 nM for compounds (**23** and **22**), respectively; microsomal or mitochondrial SQS: Ki = 5.5 and 14.8 nM for compounds (**23** and **22**), respectively). Furthermore, the antileishmanial activity of these compounds revealed IC\({}_{50}\) values in the nanomolar range when tested against promastigotes (IC\({}_{50}\) value: 14.7 and 1.7 nM for compounds (**23** and **22**), respectively) and intracellular amastigotes (IC\({}_{50}\) value: 4.0 and 0.9 nM for compounds (**23** and **22**), respectively) (after 72 h of incubation). Growth inhibition was definitely associated with the depletion of the parasite's endogenous sterols and the concomitant accumulation of exogenous cholesterol [59]. In addition, [PERSON] et al. [9] synthesized a series of 2-alkyl aminoethyl-1,1-bisphosphonate acids (compounds 9-34) as potent inhibitors of _T. cruzi_ squalene synthase with IC\({}_{50}\) values of 39.0, 5.0, 21.4, 11.9, 22.0, and 30.0 nM for compounds (**29-34**), respectively.