Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz-Fiocruz, Instituto Fernandes Figueira, Departamento de Anatomia Patológica e Citopatologia, Laboratório de Patologia Molecular, Rio de Janeiro, RJ, Brasil.
Mem Inst Oswaldo Cruz. 2020 Feb 14;115:e190389. doi: 10.1590/0074-02760190389. eCollection 2020.
Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro.
In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated.
in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses.
Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters.
N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.
由原生动物克氏锥虫引起的恰加斯病流行于拉丁美洲，主要影响低收入人群。化疗基于两种硝基化合物，但由于其疗效降低，鼓励不断寻找替代药物。我们的小组已经对萘醌及其衍生物的杀锥虫作用进行了描述，其中来源于β-拉帕醌的萘并咪唑（N1、N2 和 N3）在体外最具活性。
本研究旨在研究 N1、N2 和 N3 对急性感染小鼠的影响。
通过寄生虫学、生化、组织病理学、免疫表型、心电图（ECG）和行为分析评估化合物的体内活性。
萘并咪唑类化合物通过减少血液中锥虫的数量（8dpi）降低寄生虫血症（25-50%），但不能降低死亡率。N1 通过减少炎症来保护小鼠免受心脏损伤（15dpi）。N1 和 N2 治疗后还部分逆转了心动过缓。此外，这三种化合物均不能逆转肝肾功能损伤，也不能促进其他评估参数的改善。
N1 表现出中等的杀锥虫活性和有前途的免疫调节活性，必须在不久的将来研究其与苯并咪唑和/或抗心律失常药物联合使用的效果，以及替代制剂的疗效。
