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

  • Front Pharmacol. 2026 Apr 10:17:1780255. doi: 10.3389/fphar.2026.1780255.
J C Delorenzi  #  1  2 ,  T S Melo  1 ,  F T Silveira  #  3  4 ,  L A Carneiro  5 ,  M B Campos  3 ,  M R Cunha  6 ,  E L Ricci  1 ,  A R Fukushima  7  8 ,  S L Hurst  9 ,  S M Freeman  9 ,  M S Almeida-Saavedra  1 ,  A M Mourad  1 ,  C Sacchelli-Ramos  1 ,  L B O Delorenzi  1 ,  G B Delorenzi  1 ,  E M Saraiva  #  10
Affiliations
  • 1. Laboratory of Applied Pharmacology and Toxicology, Center of Biological and Health Sciences, Mackenzie Presbyterian University, SãoPaulo, Brazil.
  • 2. Laboratory of Drug Development, Department of Research, Development and Innovation, Hebron Pharma Group, Recife, Brazil.
  • 3. Evandro Chagas Institute (Secretariat for Health and Environmental Surveillance, Ministry of Health), Ananindeua, Brazil.
  • 4. Center for Tropical Medicine, Federal University of Pará, Belém, Brazil.
  • 5. National Primate Center, Ministry of Health, Ananindeua, PA, Brazil.
  • 6. Department of Organic Chemistry and Center of Medicinal Chemistry (CQMED), Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas, UNICAMP, SP, Brazil.
  • 7. Department of Pathology, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, SãoPaulo, Brazil.
  • 8. Universidade Santo Amaro (UNISA), SãoPaulo, Brazil.
  • 9. MindMedicine, InC, New York, NY, United States.
  • 10. Laboratory of Innate Immunity, Department of Immunology, Paulo de Góes Microbiology Institute, Universidade Federal do Rio de Janeiro (UFRJ), Rio deJaneiro, Brazil.
  • # Contributed equally.
PMID: 42038284 DOI: 10.3389/fphar.2026.1780255
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.

Keywords
18-methoxycoronaridine; Macaca fascicularis; chlorocebus aethiops; cutaneous leishmaniasis; leishmania amazonensis; murine experimental models; oral treatment; simian experimental models.
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