Tavares Grasiele S V, Mendonça Débora V C, Lage Daniela P, Antinarelli Luciana M R, Soyer Tauane G, Senna Ana J S, Matos Guilherme F, Dias Daniel S, Ribeiro Patrícia A F, Batista João P T, Poletto Joana M, Brandão Geraldo C, Chávez-Fumagalli Miguel A, Pereira Guilherme R, Coimbra Elaine S, Coelho Eduardo A F
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Pontifícia Universidade Católica de Minas Gerais, Departamento de Física e Química, Instituto de Ciências Exatas e Informática, Belo Horizonte, Minas Gerais, Brazil.
Acta Trop. 2019 Mar;191:29-37. doi: 10.1016/j.actatropica.2018.12.036. Epub 2018 Dec 23.
New therapeutics against leishmaniasis are desirable, since the current drugs applied against this disease complex presents problems, such as the toxicity, high cost and/or parasite resistance. In the present study, a new fluoroquinoline derivate, namely 7-chloro-N-(4-fluorophenethyl)quinolin-4-amine or GF1061, was evaluated regarding to its in vitro antileishmanial action against Leishmania infantum and L. amazonensis species, as well as by its toxicity in mammalian cells and efficacy in the treatment of infected macrophages. The mechanism of action of this molecule in L. amazonensis and the therapeutic efficacy in infected BALB/c mice were also evaluated. Results showed that GF1061 was effective against both parasite species, showing selectivity index (SI) of 38.7 and 42.7 against L. infantum and L. amazonensis promastigotes, respectively, and of 45.0 and 48.9 against the amastigotes, respectively. Amphotericin B (AmpB), used as control, showed SI values of 6.6 and 8.8 against L. infantum and L. amazonensis promastigotes, respectively, and of 2.2 and 2.7 against the amastigotes, respectively. The molecule was effective in treat infected macrophages, as well as it induced alterations in the mitochondrial membrane potential, increase in the reactive oxygen species production, and in the cell integrity of the parasites. Regarding to the in vivo experiments, BALB/c mice (n = 8 per group) were subcutaneously infected with 10L. amazonensis stationary promastigotes and, 60 days post-infection, they received saline or were treated during 10 days, once a day, with AmpB (1 mg/kg body weight) or GF1061 (5 mg/kg body weight). One day after the treatment, the infected tissue, spleen, liver, and draining lymph node (dLN) of the animals were collected, and the parasite load was evaluated. GF1061-treated mice, as compared to the saline and AmpB groups, showed significant reductions in the parasitism in the infected tissue (66% and 62%, respectively), liver (69% and 44%, respectively), spleen (71% and 38%, respectively), and dLN (72% and 48%, respectively). In conclusion, results suggested that GF1061 may be considered as a possible therapeutic target to be evaluated against leishmaniasis in other mammalian hosts.
由于目前用于治疗这种疾病复合体的药物存在毒性、成本高和/或寄生虫耐药性等问题，因此需要开发针对利什曼病的新疗法。在本研究中，评估了一种新的氟喹啉衍生物，即7-氯-N-(4-氟苯乙基)喹啉-4-胺或GF1061，其对婴儿利什曼原虫和亚马逊利什曼原虫的体外抗利什曼原虫作用，以及其在哺乳动物细胞中的毒性和对感染巨噬细胞的治疗效果。还评估了该分子在亚马逊利什曼原虫中的作用机制以及在感染的BALB/c小鼠中的治疗效果。结果表明，GF1061对两种寄生虫均有效，对婴儿利什曼原虫前鞭毛体和亚马逊利什曼原虫前鞭毛体的选择性指数（SI）分别为38.7和42.7，对无鞭毛体的选择性指数分别为45.0和48.9。用作对照的两性霉素B（AmpB）对婴儿利什曼原虫和亚马逊利什曼原虫前鞭毛体的SI值分别为6.6和8.8，对无鞭毛体的SI值分别为2.2和2.7。该分子对感染的巨噬细胞有效，并且它诱导线粒体膜电位改变、活性氧产生增加以及寄生虫细胞完整性改变。关于体内实验，将BALB/c小鼠（每组n = 8）皮下感染10个亚马逊利什曼原虫静止前鞭毛体，感染后60天，给它们注射生理盐水或每天一次用AmpB（1 mg/kg体重）或GF1061（5 mg/kg体重）治疗10天。治疗后一天，收集动物的感染组织、脾脏、肝脏和引流淋巴结（dLN），并评估寄生虫负荷。与生理盐水组和AmpB组相比，用GF1061治疗的小鼠在感染组织（分别为66%和62%）、肝脏（分别为69%和44%）、脾脏（分别为71%和38%）和dLN（分别为72%和48%）中的寄生虫感染率显著降低。总之，结果表明GF1061可被视为在其他哺乳动物宿主中针对利什曼病进行评估的可能治疗靶点。
