In vitro activities of iboga alkaloid congeners coronaridine and 18-methoxycoronaridine against Leishmania amazonensis

Abstract

In previous studies, we demonstrated the leishmanicide effect of coronaridine, a natural indole alkaloid isolated from stem bark of Peschiera australis (Delorenzi et al., Antimicrob. Agents Chemother. 45:1349-1354, 2001). In this study we show the leishmanicidal effect of the synthetic coronaridine and its racemic 18-methoxylated analog, 18-methoxycoronaridine. Both alkaloids revealed a potent leishmanicide effect against Leishmania amazonensis, a causative agent of cutaneous and diffuse cutaneous leishmaniasis in the New World. Despite their potent leishmanicide effect, both alkaloids were neither toxic to murine macrophages nor did they modulate their oxidative or cytokine production responses.

FIG. 1.

Effect of COR (triangles), 18-MCOR (squares), and N-methylglucamine (GLU) (circles) on amastigote survival. L. amazonensis-infected mouse peritoneal macrophages were treated with different concentrations of drugs 24 h after infection, and amastigote survival was assessed 24 h later. Results from three experiments in duplicate are shown as mean percentages ± standard errors of the means (error bars) of survival inhibition in relation to untreated controls. All the results were significant (P < 0.05).

FIG. 2.

Effect of synthetic indole alkaloids on the NO production by nonactivated (open bars) and IFN-γ-LPS-activated (hatched bars) J774.A1 macrophages. Supernatants were harvested 24 h after treatment, and nitrite concentration was estimated by Griess reaction. Data represent means with standard errors of the means (error bars) of two independent cultures done in triplicate. All compounds were tested at 10 μg/ml. Abbreviations: NA, untreated nonactivated cells; ACT, untreated activated cells.

FIG. 3.

Effect of synthetic indole alkaloids on IL-6 production by nonactivated (open bars) and IFN-γ-LPS-activated (hatched bars) J774.A1 macrophages. Supernatants were harvested 24 h after treatment, and IL-6 production was determined by ELISA. Results are from one representative experiment out of three, all done in triplicate. All compounds were tested at 10 μg/ml. Abbreviations: NA, untreated nonactivated cells; ACT, untreated activated cells; GLU, N-methylglucamine.

FIG. 4.

Effect of synthetic indole alkaloids on TNF-α production by nonactivated (open bars) and IFN-γ-LPS-activated (hatched bars) J774.A1 macrophages. Supernatants were harvested 24 h after treatment, and TNF-α production was determined by ELISA. Results are from one representative experiment out of three, all done in triplicate. All compounds were tested at 10 μg/ml. Abbreviations: NA, untreated nonactivated cells; ACT, untreated activated cells; GLU, N-methylglucamine.