Leishmaniasis, a neglected tropical disease caused by Leishmania parasites, affects millions globally. Current synthetic treatments face limitations including toxicity, cost, and resistance. Phytochemicals from medicinal plants offer promising alternatives. This mini-review synthesizes preclinical mechanisms of plant-derived compounds against leishmaniasis, focusing on mitochondrial disruption, immunomodulation, and redox imbalance.
Key Antileishmanial Mechanisms
1. Membrane Disruption & Mitochondrial Dysfunction
Hydrophobic terpenoids (e.g., essential oil components) penetrate cytoplasmic and mitochondrial membranes, causing structural damage:
Disruption of bioenergetics: Impairs ATPase activity and ATP production.
Mitochondrial swelling: Coumarin derivatives (e.g., mammea A/BB) induce membrane depolarization and ultrastructural damage in L. amazonensis.
Cell cycle arrest: Interference with lipid-protein interactions halts parasite replication.
2. Apoptosis Induction
Terpenoids trigger programmed cell death via mitochondrial pathways:
Artemisinin (sesquiterpene lactone): Causes DNA fragmentation, ATP depletion, and mitochondrial membrane collapse in L. donovani.
Ursolic acid (triterpenoid): Induces caspase-independent apoptosis in L. amazonensis, reducing lesion size in mice.
(–)-α-Bisabolol: Promotes phosphatidylserine externalization and chromatin condensation in Leishmania promastigotes.
3. Pro-Oxidant Effects & Redox Imbalance
Leishmania's single mitochondrion is vulnerable to oxidative stress:
Flavonoids: Apigenin and quercetin increase ROS, causing mitochondrial swelling and trans-Golgi disruption.
Alkaloids: Berberine induces ROS overproduction, depleting ATP and depolarizing mitochondrial membranes.
Quinones: Plumbagin inhibits trypanothione reductase, disrupting redox homeostasis.
4. Immunomodulation
Compounds enhance host immune responses:
Steroidal alkaloids (solamargine/solasonine): Activate macrophages and dendritic cells in cutaneous leishmaniasis.
Diterpenes (e.g., 12-hydroxyabietatriene): Reduce parasite load via immunostimulation in L. amazonensis-infected mice.
Apigenin: Activates host autophagy pathways in infected macrophages.
5. Biomacromolecule Interference
Lignans and neolignans target parasitic enzymes and DNA:
Diphyllin: Inhibits protein synthesis and enzyme function.
Niranthin: Forms DNA-topoisomerase I adducts, activating nucleases.
Neolignans: Disrupt plasma membranes and nuclear integrity.
Clinical Translation Challenges
Despite promising preclinical results, critical gaps remain:
No clinical trials: Limited human pharmacokinetic/pharmacodynamic data.
Combination potential: Synergy with existing drugs (e.g., amphotericin B) underexplored.
Standardization: Bioactive variability in plant extracts complicates dosing.
Future Perspectives
Mechanistic Depth: Validate mitochondrial targeting and immunomodulatory pathways.
Clinical Studies: Prioritize phase I trials for lead compounds (e.g., artemisinin derivatives).
Drug Delivery: Optimize bioavailability of hydrophobic terpenoids.
Natural Libraries: Screen unexplored plant species for novel scaffolds.
Conclusion
Since the beginning of time, dietary, medicinal, and aromatic plants, as well as their active constituents, have been used to treat a wide range of human ailments worldwide, including leishmaniasis. This practice served as the foundation for modern or contemporary medicine. Several natural compounds obtained from medicinal plants (phytochemicals) have shown strong effects against different Leishmania species in preclinical studies under both in vitro and in vivo conditions. Medicinal plant-derived compounds can effectively manage leishmaniasis by killing the parasite and preventing its growth and transmission to hosts. The mechanisms, as extracted from the scientific literature, include disruption of cytoplasmic and mitochondrial membranes, induction of apoptosis and autophagy, gene expression and immunomodulatory pathways, pro-oxidant effects (disrupting cellular redox equilibrium) with mitochondrial dysfunction, cell cycle arrest, impaired cellular bioenergetics (ATP production), protein/enzyme interaction, and coagulation of cellular contents within the Leishmania parasites. The mitochondrion of the parasite (Leishmania has only one mitochondrion) is the chief target of most of the active natural products.
Full text:
https://www.xiahepublishing.com/2835-6357/FIM-2025-00021
The study was recently published in the Future Integrative Medicine .
Future Integrative Medicine (FIM) is the official scientific journal of the Capital Medical University. It is a prominent new journal that promotes future innovation in medicine.It publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.
