Grupo de Investigación en Inmunotoxicología, Departamento de Farmacia, Universidad Nacional de Colombia, Bogotá, Colombia.
Vicerrectoría de Investigaciones, Universidad El Bosque, Bogotá, Colombia.
PLoS One. 2020 Dec 28;15(12):e0243392. doi: 10.1371/journal.pone.0243392. eCollection 2020.
Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 μg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 μg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.
利什曼病是一种被忽视的热带寄生虫病，由利什曼原虫属的细胞内原生动物引起。喹啉生物碱是芸香科植物中的次生代谢产物，对利什曼原虫具有抗寄生虫活性。N-甲基-8-甲氧基弗林德斯辛（1），从 Raputia heptaphylla 的叶子中分离出来，也称为 7-甲氧基-2,2-二甲基-2H,5H,6H-吡喃[3,2-c]喹啉-5-酮，对利什曼原虫前鞭毛体和无鞭毛体均具有抗寄生虫活性。本研究使用计算机模拟工具来识别结构类似于化合物 1 的合成喹啉生物碱，然后测试这些喹啉生物碱对利什曼（Viannia）panamensis 的体外抗寄生虫活性、感染实验性皮肤利什曼病（CL）的仓鼠的体内治疗反应以及健康供体人外周血（单核细胞）衍生的巨噬细胞（hMDMs）的体外免疫调节潜力。化合物 1（天然）、2（合成）和 8（合成）对细胞内前鞭毛体（分别为 9.9、3.4 和 1.6μg/mL 中效浓度 [EC50]）和无鞭毛体（分别为 5.07、7.94 和 1.91μg/mL EC50）均有效。化合物 1 增加了感染 hMDMs 中的一氧化氮产生，并触发了细胞内无鞭毛体的坏死相关超微结构改变，而化合物 2 刺激了 hMDMs 中的氧化分解，并在 4 小时的治疗后引起寄生虫的超微结构改变，化合物 8 未能诱导巨噬细胞调节，但选择性诱导感染 hMDMs 的细胞凋亡和细胞内寄生虫超微结构的改变。此外，合成化合物 2 和 8 改善了感染实验性 CL 的仓鼠的健康状况，而没有治疗相关不良毒性作用的证据。因此，合成化合物 2 和 8 是治疗 CL 的局部治疗的潜在候选药物。
