Oral 18-methoxycoronaridine activity in simian and murine Leishmania amazonensis infection

Abstract

Introduction – Leishmaniasis remains a major unmet medical need, with limited oral options and persistent constraints related to efficacy, tolerability, and treatment duration. We investigated 18-methoxycoronaridine (18-MC), an iboga-type indole alkaloid, as an oral candidate against Leishmania amazonensis, integrating rodent and non-human primate efficacy, toxicology, and pharmacokinetics to support clinical translation. Methods – Antileishmanial activity was first assessed in BALB/c mice treated orally with 18-MC (20 mg/kg/day). Translational efficacy was evaluated in non-human primates receiving oral 18-MC at 30 or 90 mg/kg/day for 28 days. Safety was characterized through acute and repeated-dose toxicology to establish the no-observed-adverse-effect level (NOAEL), complemented by pharmacokinetic analyses. Results – A 5-day oral regimen of 18-MC reduced murine tissue parasite burden (expressed as viable parasites per whole organ) by >99%. In Chlorocebus aethiops, 18-MC produced an exposure-dependent reduction in lesion burden, achieving ∼98% inhibition at 90 mg/kg/day, with marked re-epithelialization and no persistent clinical abnormalities. Pharmacokinetic modeling demonstrated a steep exposure–response relationship (EC50 ≈ 209 ng⋅h/mL) and a therapeutic index of approximately 5.4. The NOAEL was 50 mg/kg/day across species. Discussion – 18-MC demonstrates potent orally bioavailable antileishmanial activity with rodent–primate translational concordance and a safety profile compatible with first-in-human evaluation, supporting Phase I advancement with an estimated human equivalent dose of ∼16 mg/kg/day.