Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog

Abstract

Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC₅₀≤1.4 μM, order of activity: 2b>1>2a>3). In vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (SI) of 10-12 for 2a and SI>2.8×10² for 1, 2b and 3. 1 administered orally at 50mg/kg/day was highly active against P. berghei (in vivo inhibition compared to untreated control (IVI)=100%, mean survival time (MST)>40 days, comparable activity to chloroquine control). 1 administered orally and subcutaneously was active at 10 mg/kg/day (IVI=70-77%; MST=27-29 days). 3 exhibited high oral activity at ≥50 mg/kg/day (IVI=90-97%, MST=23-27 days). Cryptolepine (2a) administered orally and subcutaneously exhibited moderate activity at 50mg/kg/day (IVI=43-63%, MST=24-25 days). At 50 mg/kg/day, 2b administered subcutaneously was lethal to infected mice (MST=3 days) and moderately active when administered orally (IVI=45-55%, MST=25 days). 1 and 3 are promising compounds for development of antimalarials.

Anti-malarial activity of indole alkaloids isolated from Aspidosperma olivaceum

“…Novel molecules that are active in vitro have been identified in Aspidosperma parvifolium, A. olivaceum, Aspidosperma vargasii , and Aspidosperma ramiflorum . Extracts from A. vargasii and A. olivaceum have been tested and found to be active in mice infected with P. berghei [35] . …”

Aspidosperma Species as Sources of Antimalarials. Part III. A Review of Traditional Use and Antimalarial Activity

“…Ellipticine was also more active than olivacine in an evaluation of the effects in P. berghei-infected mice. Remarkably, 100 % parasitemia suppression was observed at an oral dose of 50 mg/kg/day (four days), and no mortality or other signs of toxicity were reported [48]. Ellipticine (1) and its derivatives were described as the most active compounds, with IC 50 values < 1 µg/mL (range 0.08 to 0.47 µg/mL), in a series of 184 randomly selected compounds belonging to several classes of natural products, either from plants or from marine organisms, or prepared as intermediates during the synthesis or semisynthesis of isolated products that were assayed against the P. falciparum FcM29 strain [52].…”

“…Several of these alkaloids have been evaluated for various biological/pharmacological effects [30]. A total of 20 Aspidosperma alkaloids have been assayed for antimalarial activity and have been isolated by Brazilian researchers, one from A. desmanthum [45], one from A. vargasii [45], one from A. parvifolium [27,46], five from A. ulei [47], and one from A. olivaceum [48]; additionally, a French-Bolivian group has evaluated 11 alkaloids from A. megalocarpon and A. pyrifolium [41]. Ellipticine (1) and aspidocarpine (2) (l " Fig.…”

In vitro and in vivo anti-malarial activity of limonoids isolated from the residual seed biomass from Carapa guianensis (andiroba) oil production

“…The in vitro inhibition of the growth of P. falciparum K1 from these cultures by limonoids 1 - 4 and derivative 5 was evaluated as described previously [27]. Briefly, this procedure involved preparing 5 mg/mL stock solutions of each compound in dimethyl sulfoxide (DMSO).…”

“…Each sample was evaluated in duplicate and the test plate was incubated for 48 h at 37°C. After incubation, quantification of parasites was achieved by optical microscopy on blood smears from each well [27]. …”