ArticleMemorias do Instituto Oswaldo Cruz2025
Miltefosine analogues with comparable antileishmanial activity and significantly reduced macrophage cytotoxicity.
Article in Memorias do Instituto Oswaldo Cruz, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Kinetoplast-Directed Therapies: A Selective Mitochondrial Approach to Combat Leishmaniasis.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts.Journal of medicinal chemistry · 2025Article
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Authors and funding
10 authors.
Funding
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Abstract
backgroundMiltefosine (MIL) is the only oral drug approved for leishmaniasis treatment, but its use is limited by gastrointestinal toxicity. Novel alkylphospholipid analogues may provide safer and more effective alternatives.
objectivesThis study aimed to assess the antileishmanial activity, cytotoxicity, and membrane interactions of three MIL analogues TC387, TC388, and TC437 against Leishmania amazonensis.
methodsAntileishmanial and cytotoxic activities were evaluated in L. amazonensis, J774.A1 macrophages, and erythrocytes. Membrane interactions were characterized using spin-label electron paramagnetic resonance (EPR) spectroscopy.
findingsTC387, TC388, and TC437 demonstrated EC50 values of 10-16 µM for intracellular amastigotes, compared to 17 µM for MIL, with selectivity indices (SI) ranging from 43-163, significantly higher than MIL's SI of 5. EPR data revealed that the analogues increased membrane protein dynamics and caused greater disruption at the lipid-protein interface of parasite membranes relative to MIL. This disruption likely enhances pore formation, ion leakage, and reactive oxygen species (ROS) production, leading to parasite death. MAIN
conclusionsThe MIL analogues TC387, TC388, and TC437 exhibited superior SI and comparable or slightly enhanced antileishmanial activity relative to MIL, along with very low hemolytic potential. These findings support further investigation of these analogues as promising oral therapeutic candidates for leishmaniasis.
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