Alonso Lais, Lemes Laís Flávia Nunes, Magoulas George E, Costa Brenda de Lucena, Gomes Rodrigo Saar, Dorta Miriam Leandro, Bolognesi Maria Laura, Romeiro Luiz Antonio Soares, Calogeropoulou Theodora, Alonso Antonio
Universidade Federal de Goiás, Instituto de Física, Goiânia, GO, Brasil.
Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação em Medicina Tropical, Laboratório de Desenvolvimento de Inovações Terapêuticas, Brasília, DF, Brasil.
Mem Inst Oswaldo Cruz. 2025 May 26;120:e240219. doi: 10.1590/0074-02760240219. eCollection 2025.
Miltefosine (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.
This study aimed to assess the antileishmanial activity, cytotoxicity, and membrane interactions of three MIL analogues TC387, TC388, and TC437 against Leishmania amazonensis.
Antileishmanial 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.
TC387, 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.
The 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.
米替福新（MIL）是唯一被批准用于治疗利什曼病的口服药物，但其使用受到胃肠道毒性的限制。新型烷基磷脂类似物可能提供更安全、更有效的替代方案。
本研究旨在评估三种米替福新类似物TC387、TC388和TC437对亚马逊利什曼原虫的抗利什曼活性、细胞毒性和膜相互作用。
在亚马逊利什曼原虫、J774.A1巨噬细胞和红细胞中评估抗利什曼活性和细胞毒性。使用自旋标记电子顺磁共振（EPR）光谱对膜相互作用进行表征。
与米替福新的17 μM相比，TC387、TC388和TC437对细胞内无鞭毛体的半数有效浓度（EC50）值为10-16 μM，选择性指数（SI）范围为43-163，显著高于米替福新的SI值5。EPR数据显示，与米替福新相比，这些类似物增加了膜蛋白动力学，并在寄生虫膜的脂-蛋白界面引起更大的破坏。这种破坏可能会增强孔形成、离子泄漏和活性氧（ROS）产生，从而导致寄生虫死亡。
米替福新类似物TC387、TC388和TC437表现出优于米替福新的SI，抗利什曼活性相当或略有增强，且溶血潜力极低。这些发现支持进一步研究这些类似物作为利什曼病有前景的口服治疗候选药物。
