Barros Freitas Luiz Alberto, Caroline da Silva Santos Aline, de Cássia Silva Gedália, Nayara do Nascimento Albuquerque Franciely, Silva Elis Dionísio, Alberto de Simone Carlos, Alves Pereira Valéria Rêgo, Alves Luiz Carlos, Brayner Fabio André, Lima Leite Ana Cristina, de Moraes Gomes Paulo André Teixeira
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-535, Recife, PE, Brazil.
Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
Chem Biol Interact. 2021 Aug 25;345:109561. doi: 10.1016/j.cbi.2021.109561. Epub 2021 Jun 24.
Neglected diseases are a group of transmissible diseases that occur mostly in countries in tropical climates. Among this group, Chagas disease and leishmaniasis stand out, considered threats to global health. Treatment for these diseases is limited. Therefore, there is a need for new therapies against these diseases. In this sense, our proposal consisted of developing two series of compounds, using a molecular hybridization of the heterocyclic isatin and thiazole. The isatin and thiazole ring are important scaffold for several biological disorders, including antiparasitic ones. Herein, thiazolyl-isatin has been synthesized from respective thiosemicarbazone or phenyl-thiosemicarbazone, being some of these new thiazolyl-isatin toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 2e (IC = 4.43 μM), 2j (IC = 2.05 μM), 2l (IC = 4.12 μM) and 2m (1.72 μM) showed the best anti-T. cruzi activity for trypomastigote form presenting a selectivity index higher than Benznidazole (BZN). Compounds 2j, 2l and 2m were able to induce a significantly labelling compatible with necrosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with the compound 2m from IC concentrations, promoted changes in the shape, flagella and surface of body causing of the parasite dead. Concerning leishmanicidal evaluation against L. amazonensis and L. infantum, compounds 2l (IC = 7.36 and 7.97 μM, respectively) and 2m (6.17 and 6.04 μM, respectively) showed the best activity for promastigote form, besides showed a higher selectivity than Miltefosine. Thus, compounds 2l and 2m showed dual in vitro trypanosomicidal and leishmanicidal activities. A structural activity relationship study showed that thiazolyl-isatin derivatives from phenyl-thiosemicarbazone (2a-m) were, in general, more active than thiazolyl-isatin derivatives from thiosemicarbazone (1a-g). Crystallography studies revealed a different configuration between series 1a-g and 2a-m. The configuration and spatial arrangement divergent between the two sub-series could explain the improved biological activity profile of 2a-m sub-series.
被忽视的疾病是一类主要发生在热带气候国家的传染性疾病。在这类疾病中，恰加斯病和利什曼病尤为突出，被视为对全球健康的威胁。针对这些疾病的治疗方法有限。因此，需要研发针对这些疾病的新疗法。从这个意义上讲，我们的方案是利用杂环异吲哚酮和噻唑的分子杂交来开发两个系列的化合物。异吲哚酮环和噻唑环是多种生物紊乱（包括抗寄生虫紊乱）的重要骨架。在此，噻唑基异吲哚酮是由相应的硫代半卡巴腙或苯基硫代半卡巴腙合成的，其中一些新的噻唑基异吲哚酮对锥鞭毛体有毒，而不影响巨噬细胞的活力。在这个系列中，化合物2e（IC = 4.43 μM）、2j（IC = 2.05 μM）、2l（IC = 4.12 μM）和2m（1.72 μM）对锥鞭毛体形式表现出最佳的抗克氏锥虫活性，其选择性指数高于苯并硝唑（BZN）。化合物2j、2l和2m能够在锥鞭毛体中诱导出与坏死相符的显著标记。扫描电子显微镜分析表明，用IC浓度的化合物2m处理克氏锥虫锥鞭毛体细胞，会导致寄生虫身体的形状、鞭毛和表面发生变化，从而导致其死亡。关于对亚马逊利什曼原虫和婴儿利什曼原虫的杀利什曼活性评估，化合物2l（IC分别为7.36和7.97 μM）和2m（分别为6.17和6.04 μM）对前鞭毛体形式表现出最佳活性，并且比米替福新表现出更高的选择性。因此，化合物2l和2m表现出双重体外抗锥虫和杀利什曼活性。结构活性关系研究表明，来自苯基硫代半卡巴腙的噻唑基异吲哚酮衍生物（2a - m）一般比来自硫代半卡巴腙的噻唑基异吲哚酮衍生物（1a - g）更具活性。晶体学研究揭示了1a - g系列和2a - m系列之间的不同构型。两个子系列之间构型和空间排列的差异可以解释2a - m子系列改善的生物活性谱。
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