Anti-malarial activity of indole alkaloids isolated from Aspidosperma olivaceum

Abstract

BackgroundSeveral species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum.MethodsThe activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei.ResultsAll six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 μg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active.ConclusionUsing a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.

Ethnopharmacological evaluation of medicinal plants used against malaria by quilombola communities from Oriximiná, Brazil

“…The diversity of species often known by the same vulgar name (´carapanauba') that are used for the same purpose (malaria) suggests that the morphological aspects that characterize the ethnospecies are sufficient to also characterize its therapeutic use, independently of which species is collected. However, the most cited species in the Amazon used as a remedy against malaria is A. nitidum, which has proven to be the most active species based on its specific activity (Penna- Coutinho et al, 2013), superior than the other species less cited as antimalarial, such as A. ollivaceum, also studied by the same group (Chierrito et al, 2014). Other species tested showed variable in vitro activity against the P. falciparum with IC 50 values ranging from 0.019 to 42 µM (Brandão et al, 1985;Carvalho et al, 1992;Mitaine-Offer et al, 2002;Paula et al, 2014;Torres et al, 2013).…”

Aspidosperma species as sources of anti-malarials: uleine is the major anti-malarial indole alkaloid from Aspidosperma parvifolium (Apocynaceae)

“…Higher IC 50 values were determined for all the samples against W2 parasite by the radioisotopic method than by the microscopic method and it was approximately ten-fold higher for the alkaloid fraction and uleine. For the purpose of comparison, the data on the anti-malarial activity of apparicine, aspidocarpine, and ellipticine, the only previously assayed alkaloids [37, 38] out of the 16 here identified in Aspidosperma parvifolium , are included in Table 2.…”

“…It is interesting to call attention for the fact that, only three (apparicine, aspidocarpine and ellipticine) out of the 16 identified alkaloids in the trunk bark of Aspidosperma parvifolium were previously evaluated against P. falciparum [37, 38]. Ellipticine is the most active alkaloid amongst those shown in Table 2 but it is highly cytotoxic while uleine was not active against a panel of tumoral cells [18].…”

A validated and densitometric HPTLC method for the simultaneous quantification of reserpine and ajmalicine in Rauvolfia serpentina and Rauvolfia tetraphylla

“…Indole alkaloids are the bioactive compounds derived from plants which possess an array of pharmacological properties such as anticancer (Wang et al, 2015;Zhu et al, 2015), antimalarial (Chierrito et al, 2014), antimicrobial (Cheenpracha et al, 2014) and cerebroprotective (Biradar et al, 2013) properties. The major bioactive alkaloids reported from various Rauvolfia species are reserpine, reserpiline, ajmaline, ajamalacine, rauvolfinine, serpinine, serpentine, serpentinine, yohimbine, vomilenine, picrinine, vinorine, norseredamine, seredamine (Stöckigt et al, 1981;Batista et al, 1996;Duez et al, 1986;De Bruyn et al, 1989;Kato et al, 2002;Bindu et al, 2014).…”