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][1350][1351][1352][1353][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.Leishmaniasis, a disease that affects 12 million people worldwide, presents broad clinical manifestations, ranging from a single localized ulcer to fatal hepatosplenomegaly, depending on the parasite species and the immunological status of the host (42). Recently, a dramatic increase in leishmaniasis cases was observed, specifically associated with human immunodeficiency virus infection (41, 42).The drugs currently available for leishmaniasis treatmentpentavalent antimonials, amphotericin B, and pentamidinepresent many severe side effects, are expensive, and are frequently ineffective. Furthermore, large-scale clinical antinomy resistance has been reported (5,10,21,28). All these problems, together with the lack of a safe and effective vaccine, emphasize the importance of the development of new drugs against leishmaniasis.Recently, we described the antiparasite effect of coronaridine (COR), isolated from the stem of the Peschiera australis shrub, against Leishmania amazonensis promastigotes and intracellular amastigotes (7,12). COR is an iboga-type indole alkaloid found in many species of the plant kingdom. Like others iboga alkaloids, COR was investigated for a wide variety of pharmacological effects, such as antitumor, anti-inflammatory, and bactericidal activities (23,37,39), as well as a stimulatory action on the central nervous system. COR has been studied for its potential antiaddictive properties (11,13,14,17,29), showing an effective decrease in morphine, cocaine, ethanol, and nicotine self-administration in laboratory animals analogous to that observed with ibogaine (reviewed in references 13 and 14). Because of side effects such as tremor, cerebellar neurotoxicity, and bradycardia associated with ibogaine and COR, an 18-methoxylated COR analog was developed with the goal of reducing adverse effects. In preclinical studies, 18-methoxycoronaridine (18-MCOR) exerted few to none of the side effects associated with ibogaine or COR (reviewed in references 15, 16, and 32).In the present study, we describe the leishmanicidal activities of the synthetic COR and its analog, 18-MCOR, which were similar to the antiparasite effect of the natural COR. The synthetic compounds, like the natural COR, did not induce nitric oxide production, nor did they stimulate the synthesis of interleukin 6 (IL-6),...