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In vitro tripanocidal effect of 1,8-dioxooctahydroxanthenes (xanthenodiones) and tetraketones and improvement of cardiac parameters in vivo.
Journal of Global Antimicrobial Resistance ( IF 3.7 ) Pub Date : 2020-05-14 , DOI: 10.1016/j.jgar.2020.04.005
Ana Paula de Jesus Menezes 1 , Milene Lopes da Silva 2 , Wagner Luiz Pereira 2 , Guilherme de Paula Costa 1 , Aline Luciano Horta 1 , Andréa Aparecida Santos Mendonça 3 , Ana Claudia Alvarenga Carneiro 1 , Debora Maria Soares de Souza 1 , Rômulo Dias Novaes 3 , Róbson Ricardo Teixeira 2 , André Talvani 1
Affiliation  

Objective

Trypanosoma cruzi infection affects millions of people worldwide, and the drugs available for its treatment have limited efficacy. 1,8-Dioxooctahydroxanthenes and tetraketones are compounds with important biological applications. The aim of this study was to assess the trypanocidal and inflammatory activities of nine 1,8-dioxooctahydroxanthenes (19) and three tetraketones (1012).

Methods and results

By in vitro killing assay, three compounds were able to eliminate CL TdTomato expressing strain of T. cruzi, 9 (IC50 = 30.65 μM), 10 (IC50 = 14.11 μM), and 11 (IC50 = 26.43 μM). However, only 9 was not toxic to Vero cells. Next, to evaluate the in vivo antitrypanosomal and immunological efficacy of 9, Swiss mice were infected with the Y and CL strains of T. cruzi and treated for 10 days with 50 mg/kg of 9. This compound reduced the cardiac inflammatory infiltration in animals infected with both strains. Rank's ligand (RankL), CCL2, and interferon (IFN)-γ were measured in the cardiac tissue homogenate of the Y-strain-infected animals, and no interference of 9 was observed. However, compound 9 increased the RankL and interleukin (IL)-10 levels in CL-infected mice. No hepatic and renal toxicity was observed.

Conclusion

Our findings showed that 1,8-dioxooctahydroxanthene has antiparasitic effect and ameliorates the cardiac inflammatory parameters related to T. cruzi infection.



中文翻译:

1,8-二氧杂八氢氧杂蒽(黄酮二酮)和四酮的体外杀螨作用和体内心脏参数的改善。

目的

克氏锥虫感染影响全球数百万人,可用于治疗的药物疗效有限。1,8-二氧杂八氢黄嘌呤和四酮是具有重要生物学应用的化合物。这项研究的目的是评估9种1,8-二氧杂八氢黄嘌呤(19)和3种四酮(1012)的锥虫杀虫剂和炎性活性。

方法与结果

通过体外杀伤试验,三种化合物能够消除表达CL TdTomato的克氏锥虫菌株,分别为9(IC 50  = 30.65μM),10(IC 50  = 14.11μM)和11(IC 50  = 26.43μM)。但是,只有9种对Vero细胞无毒。接下来,为了评估9的体内抗胰岛蛋白体和免疫学功效,瑞士小鼠感染了克鲁氏耶尔森氏菌的Y和CL株,并用50 mg / kg的9进行了10天的治疗。该化合物减少了同时感染两种病毒的动物的心脏炎症浸润。在Y株感染动物的心脏组织匀浆中测量了Rank配体(RankL),CCL2和干扰素(IFN)-γ,未观察到9种干扰。但是,化合物9增加了CL感染小鼠的RankL和白介素(IL)-10水平。没有观察到肝和肾毒性。

结论

我们的研究结果表明,1,8-二氧杂八氢黄嘌呤具有抗寄生虫作用,并可以改善与克鲁氏锥虫感染有关的心脏炎症参数。

更新日期:2020-05-14
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