In vitro tripanocidal effect of 1,8-dioxooctahydroxanthenes (xanthenodiones) and tetraketones and improvement of cardiac parameters in vivo.,Journal of Global Antimicrobial Resistance

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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 (1–9) and three tetraketones (10–12).

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（1 – 9）和3种四酮（10 – 12）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。