Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.
Fundação Oswaldo Cruz (Fiocruz), Instituto de Tecnologia em Fármacos Farmanguinhos, Rio de Janeiro, Brazil.
Chem Biol Drug Des. 2024 May;103(5):e14535. doi: 10.1111/cbdd.14535.
Despite efforts, available alternatives for the treatment of leishmaniasis are still scarce. In this work we tested a class of 15 quinolinylhydrazone analogues and presented data that support the use of the most active compound in cutaneous leishmaniasis caused by Leishmania amazonensis. In general, the compounds showed activity at low concentrations for both parasitic forms (5.33-37.04 μM to promastigotes, and 14.31-61.98 μM to amastigotes). In addition, the best compound (MHZ15) is highly selective for the parasite. Biochemical studies indicate that the treatment of promastigotes with MHZ15 leads the loss of mitochondrial potential and increase in ROS levels as the primary effects, which triggers accumulation of lipid droplets, loss of plasma membrane integrity and apoptosis hallmarks, including DNA fragmentation and phosphatidylserine exposure. These effects were similar in the intracellular form of the parasite. However, in this parasitic form there is no change in plasma membrane integrity in the observed treatment time, which can be attributed to metabolic differences and the resilience of the amastigote. Also, ultrastructural changes such as vacuolization suggesting autophagy were observed. The in vivo effectiveness of MHZ15 in the experimental model of cutaneous leishmaniasis was carried out in mice of the BALB/c strain infected with L. amazonensis. The treatment by intralesional route showed that MHZ15 acted with great efficiency with significantly reduction in the parasite load in the injured paws and draining lymph nodes, without clinical signs of distress or compromise of animal welfare. In vivo toxicity was also evaluated and null alterations in the levels of hepatic enzymes aspartate aminotransferase, and alanine aminotransferase was observed. The data presented herein demonstrates that MHZ15 exhibits a range of favorable characteristics conducive to the development of an antileishmanial agent.
尽管已经做出了努力，但治疗利什曼病的可用替代品仍然稀缺。在这项工作中，我们测试了一类 15 个喹啉腙类似物，并提供了支持使用对亚马逊利什曼原虫引起的皮肤利什曼病最有效的化合物的数据。一般来说，这些化合物在低浓度下对两种寄生虫形式（5.33-37.04 μM 对前鞭毛体，14.31-61.98 μM 对无鞭毛体）都具有活性。此外，最好的化合物（MHZ15）对寄生虫具有高度选择性。生化研究表明，用 MHZ15 处理前鞭毛体导致线粒体电位丧失和 ROS 水平升高，这是主要的影响，从而引发脂滴积累、质膜完整性丧失和凋亡特征，包括 DNA 片段化和磷脂酰丝氨酸暴露。这些影响在寄生虫的体内形式中是相似的。然而，在这种寄生虫形式中，在观察到的治疗时间内，质膜完整性没有变化，这可以归因于代谢差异和无鞭毛体的弹性。此外，还观察到了超微结构变化，如提示自噬的空泡化。在感染了亚马逊利什曼原虫的 BALB/c 品系小鼠的皮肤利什曼病实验模型中，进行了 MHZ15 的体内有效性研究。通过皮内途径治疗表明，MHZ15 具有极高的疗效，显著减少了受伤爪子和引流淋巴结中的寄生虫负荷，且动物没有出现不适或健康状况受损的临床症状。还评估了体内毒性，未观察到天冬氨酸转氨酶和丙氨酸转氨酶的肝酶水平发生变化。本文提供的数据表明，MHZ15 具有一系列有利的特征，有利于开发抗利什曼病药物。
