Departamento de Morfologia e Fisiologia Animal, Universidade Federal Rural de Pernambuco (UFRPE), Recife, Brazil; Centro Acadêmico de Vitória, Universidade Federal de Pernambuco (UFPE), Vitória de Santo Antão, Brazil.
Departamento de Microbiologia, Centro de Pesquisas Aggeu Magalhães, Universidade Federal de Pernambuco (UFPE), Recife, Brazil.
J Glob Antimicrob Resist. 2020 Sep;22:414-421. doi: 10.1016/j.jgar.2020.02.028. Epub 2020 Mar 9.
In the prospection of possible agents against neglected diseases, thiazole compounds are presented as promising candidates and are known to have activity against trypanosomatid parasites. Thus, this work aimed to evaluate the effects of thiazole compounds on Leishmania infantum, the aetiological agent of visceral leishmaniasis.
Thiazole compounds (five thiazoacetylpyridines [TAPs-01, -04, -05, -06, -09) and five thiazopyridines [TPs-01, -04, -05, -06, -09]) were tested regarding their leishmanicidal activity on both promastigote and amastigote forms of L. infantum. Cytotoxicity was tested using peritoneal macrophages of BALB/c mice. Ultrastructural analyses were performed to identify possible intracellular targets of the most effective compound on promastigote forms. To observe routes that can clarify the possible mechanism of action of the compounds on the intracellular amastigote forms, the nitrite dosage was performed.
All compounds inhibited the growth of promastigote and presented low cytotoxicity, being more selective to the parasite than to mammalian cells. All compounds tested were able to decrease macrophage infection. There was a significant decrease in the survival rate of the amastigote when compared with the untreated cells, with TAP-04 presenting the best index. TAP-04 induced ultrastructural changes that are related to cell death by apoptosis. None of the macrophage groups infected with L. infantum and subsequently treated showed increased nitrite release.
The low toxicity to mammalian cells and the leishmanicidal activity observed demonstrate that the synthesis of drugs based in thiosemicarbazone nucleus, thiazole and pyridine derivatives are promising for the treatment of visceral leishmaniasis.
在寻找针对被忽视疾病的潜在药物的过程中，噻唑类化合物被认为是很有前途的候选药物，因为它们对原生动物寄生虫具有活性。因此，本工作旨在评估噻唑类化合物对利什曼原虫（内脏利什曼病的病原体）的影响。
噻唑类化合物（五种噻唑乙酰基吡啶[TAPs-01、-04、-05、-06、-09]和五种噻唑吡啶[TPs-01、-04、-05、-06、-09]）对利什曼原虫的前鞭毛体和无鞭毛体形式进行了杀利什曼原虫活性测试。用 BALB/c 小鼠腹腔巨噬细胞测试细胞毒性。进行超微结构分析以鉴定对前鞭毛体形式最有效的化合物的可能细胞内靶标。为了观察可以阐明化合物对细胞内无鞭毛体形式的可能作用机制的途径，进行了亚硝酸盐剂量测定。
所有化合物均抑制前鞭毛体的生长，并表现出低细胞毒性，对寄生虫的选择性高于对哺乳动物细胞。所有测试的化合物都能够降低巨噬细胞的感染率。与未处理的细胞相比，无鞭毛体的存活率显著降低，其中 TAP-04 表现出最好的指数。TAP-04 诱导的超微结构变化与细胞凋亡引起的细胞死亡有关。与未感染 L. infantum 且未随后进行治疗的巨噬细胞组相比，感染 L. infantum 且随后进行治疗的巨噬细胞组中亚硝酸盐的释放没有增加。
对哺乳动物细胞的低毒性和观察到的杀利什曼原虫活性表明，基于硫代半缩酮核、噻唑和吡啶衍生物的药物合成对于治疗内脏利什曼病具有很大的前景。
