Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae)

Abstract

We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.

FIG. 1.

Chemical structures of simalikalactone E (compound 1) and simalikalactone D (compound 2).

FIG. 2.

Structure of SkE obtained from X-ray diffraction experiment.

FIG. 3.

Impact of SkE on the eythrocytic cycle of P. falciparum. A parasite culture synchronized on a 6-h period was subjected to 8-h pulses of SkE at the IC₅₀ (gray bars) and 1/10 the value (white bars). After the pulse, the culture was washed and returned to normal culture conditions until the beginning of the second erythrocytic cycle, and then parasitemia was determined. The scale bar at the top of the figure shows time (in hours). Major events along the eythrocytic cycle are shown. The dotted line shows protein synthesis, and the solid black line shows DNA synthesis. This figure was adapted from the Annals of Tropical Medicine and Parasitology (2) with the permission of the publisher.

FIG. 4.

Bivariate analysis (Kaplan-Meier curves and log rank tests) for survival time. Survival of treated mice was monitored for 21 days (inoculation at day 0). The antimalarial treatment and route were as follows: chloroquine (CQ) (1, 5, or 10 mg/kg/day for 4 days); simalikalactone E (SKE) (0.5, 1, 5, 10, or 20 mg/kg/day); PO, oral route; IP, intraperitoneal route. When the line does not reach 0, the mice were still alive at day 21.