**3. Conclusion**

*P. falciparum* isoprenoid-related enzymes, nerolidol was used to inhibit the OPPS/PSY activity

As we have seen, some MEP pathway and isoprenoid pathway inhibitors show good antimalarial activity and produce important metabolic alterations in *P. falciparum.* Different authors asked if using terpenes individually or in combination with other drugs could be a good strategy to treat malaria. It is well established that fosmidomycin and clindamycin, when combined, produce a synergistic activity *in vitro* and *in vivo* [88], and several drugs which act at different points of the MEP/isoprenoid showed supra-additive *in vitro* effects when combined [56]. These kinds of drug combination studies are useful for a better understanding of the interactions between the different intermediates of the MEP and isoprenoid pathways and to evaluate its antimalarial potential. Fosmidomycin, risedronate, nerolidol and squalestatin (supposed to be a phytoene synthase inhibitor) are drugs which are believed to act in different cellular compartments, and all of them seem to inhibit at least one point related to isoprenoid metabolism [56]. Except nerolidol-risedronate, most binary combinations between fosmidomycin, risedronate, nerolidol and squalestatin showed a supra-additive effect [56]. Probably it is because they target different enzymes in the same biosynthetic pathway. On the other hand, nerolidol and risedronate when combined showed a sub-additive effect. It was suggested that this fact could be explained because both compounds affect the same target of isoprenoid pathways [56]. Nerolidol affects the synthesis of several isoprenoid compounds,

Due to the terpenes effectiveness to inhibit the *P. falciparum* growth *in vitro*, several studies have been focused on studying these effects on experimental models of malaria by *P. berghei* infection. Nerolidol for example, being administered on Balb/c mice at a dose 2000 mg/kg/ day by oral and intranasal via, had an inhibitory effect on the *P. berghei* ANKA growth, since the parasitemia were reduced and the survival rates were increased significantly with the nerolidol treatment [89]. Also, some derivatives of 4-nerolidylcatechol, at oral doses of 50 mg/ kg/day, had suppressed *P. berghei* NK65 in infected BALB/c mice by 44%, showing marked

On the other hand, some metabolites derived from limonene, such as perillyl alcohol, have also been shown to be effective against the severe conditions development caused by *P. berghei* infection. C57BL/6 mice infected with *P. berghei* ANKA and treated with 500 mg/kg/day intranasal via had a significant increase in survival rates, showing a preventive effect against

Furthermore, plant extracts that contain several terpenes have also been tested on experimental models. The antimalarial activity of ethanolic bark extract of *A. lebbeck* was determined. Phytochemical screening revealed the presence of alkaloids, flavonoids, phenols, saponins,

Limonoids isolated from the residual seed biomass from *Carapa guianensis* were tested against *P. berghei* and 6α-acetoxy-gedunin was more active than 7-deacetoxy-7-oxogedunin. At oral doses of 50 and 100 mg/kg/day, 6α-acetoxy-gedunin suppressed parasitemia versus untreated

controls by 40 and 66%, respectively, evidencing a clear dose response [92].

including protein isoprenylation as well as risedronate [55, 67].

improvement over the parasite's growth [90].

terpenes, and phytosterols [91].

the experimental cerebral malaria development [82].

H]FPP and [14C]IPP as substrates. OPPS/PSY activity was competitively inhibited by

using [3

48 Terpenes and Terpenoids

nerolidol (*Ki* 15 ̴ nM) [61].

*Plasmodium* spp. has an organelle, the apicoplast, which is essential for the development of the parasite because it is linked to two metabolic pathways, one of which is the isoprenoid biosynthesis that is different in several steps from the isoprenoid pathway in the vertebrate host. The biosynthesis pathway is an important target for evaluating new antimalarial drugs and the terpenes for being derived from the isoprenoid pathway and having a similar structure can interfere in the synthesis of isoprenoids and should be evaluated as antimalarial potentials.
