Sousa Jessica K T, Antinarelli Luciana M R, Mendonça Débora V C, Lage Daniela P, Tavares Grasiele S V, Dias Daniel S, Ribeiro Patrícia A F, Ludolf Fernanda, Coelho Vinicio T S, Oliveira-da-Silva João A, Perin Luísa, Oliveira Bianka A, Alvarenga Denis F, Chávez-Fumagalli Miguel A, Brandão Geraldo C, Nobre Vandack, 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, 30130-100 Belo Horizonte, Minas Gerais, Brazil.
Pontifícia Universidade Católica de Minas Gerais, Departamento de Física e Química, Instituto de Ciências Exatas e Informática, 30535-901 Belo Horizonte, Minas Gerais, Brazil.
Parasitol Int. 2019 Dec;73:101966. doi: 10.1016/j.parint.2019.101966. Epub 2019 Jul 27.
The identification of new therapeutics to treat leishmaniasis is desirable, since available drugs are toxic and present high cost and/or poor availability. Therefore, the discovery of safer, more effective and selective pharmaceutical options is of utmost importance. Efforts towards the development of new candidates based on molecule analogs with known biological functions have been an interesting and cost-effective strategy. In this context, quinoline derivatives have proven to be effective biological activities against distinct diseases. In the present study, a new chloroquinoline derivate, AM1009, was in vitro tested against two Leishmania species that cause leishmaniasis. The present study analyzed the necessary inhibitory concentration to preclude 50% of the Leishmania promastigotes and axenic amastigotes (EC value), as well as the inhibitory concentrations to preclude 50% of the murine macrophages and human red blood cells (CC and RBC values, respectively). In addition, the treatment of infected macrophages and the inhibition of infection using pre-treated parasites were also investigated, as was the mechanism of action of the molecule in L. amazonensis. To investigate the in vivo therapeutic effect, BALB/c mice were infected with L. amazonensis and later treated with AM1009. Parasitological and immunological parameters were also evaluated. Clioquinol, a known antileishmanial quinoline derivate, and amphotericin B (AmpB), were used as molecule and drug controls, respectively. Results in both in vitro and in vivo experiments showed a better and more selective action of AM1009 to kill the in vitro parasites, as well as in treating infected mice, when compared to results obtained using clioquinol or AmpB. AM1009-treated animals presented significantly lower average lesion diameter and parasite burden in the infected tissue and organs evaluated in this study, as well as a more polarized antileishmanial Th1 immune response and low renal and hepatic toxicity. This result suggests that AM1009 should be considered a possible therapeutic target to be evaluated in future studies for treatment against leishmaniasis.
鉴于现有治疗利什曼病的药物有毒且成本高昂和/或供应不足，确定新的治疗方法是很有必要的。因此，发现更安全、更有效和更具选择性的药物选择至关重要。基于具有已知生物学功能的分子类似物开发新候选药物的努力一直是一种有趣且具有成本效益的策略。在这方面，喹啉衍生物已被证明对多种不同疾病具有有效的生物活性。在本研究中，一种新的氯喹啉衍生物AM1009针对两种引起利什曼病的利什曼原虫进行了体外测试。本研究分析了抑制50%利什曼原虫前鞭毛体和无菌无鞭毛体所需的抑制浓度（EC值），以及抑制50%小鼠巨噬细胞和人类红细胞所需的抑制浓度（分别为CC和RBC值）。此外，还研究了感染巨噬细胞的治疗以及使用预处理寄生虫对感染的抑制作用，以及该分子在亚马逊利什曼原虫中的作用机制。为了研究体内治疗效果，将BALB/c小鼠感染亚马逊利什曼原虫，随后用AM1009进行治疗。还评估了寄生虫学和免疫学参数。分别使用已知的抗利什曼喹啉衍生物氯碘羟喹和两性霉素B（AmpB）作为分子对照和药物对照。与使用氯碘羟喹或AmpB获得的结果相比，体外和体内实验结果均显示AM1009在杀死体外寄生虫以及治疗感染小鼠方面具有更好、更具选择性的作用。在本研究评估的感染组织和器官中，接受AM1009治疗的动物平均病变直径和寄生虫负荷显著降低，同时具有更极化的抗利什曼Th1免疫反应以及较低的肾毒性和肝毒性。这一结果表明，AM1009应被视为未来研究中治疗利什曼病可能的治疗靶点进行评估。
