Antiproliferative activity of the dibenzylideneacetone derivate (E)-3-ethyl-4-(4-nitrophenyl)but‑3-en-2-one in Trypanosoma cruzi
Graphical abstract
Introduction
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, affecting 6–7 million people worldwide (WHO, 2019). This protozoan parasite displays three distinct evolutionary relevant forms: the epimastigote, found inside the hematophagous insect; the trypomastigote, which is the infective form found in the insect vector and in the blood circulation of the mammalian host; and the amastigote, found intracellularly in tissues of the mammalian host. The epimastigote and amastigote are the replicative forms of the parasite (Alves et al., 2007; Nogueira et al., 2007).
Infection by T. cruzi has two clinical phases: the acute phase characterized by high parasitemia; and the chronic phase, which is long and progressive whereby symptoms can manifest after some years. The treatment of Chagas disease is performed with two drugs, nifurtimox or benznidazole. However, they have several side effects and limited therapeutic potential (Coura, 2009; Izumi et al., 2011).
Several studies have shown that synthetic compounds have great potential for the treatment of Chagas’ disease as thiazoles, β-lapachone, β-carbolines, quinoxalines (Cogo et al., 2015; de Oliveira Filho et al., 2017; Garavaglia et al., 2018; Moreno-Viguri and Pérez-Silanes, 2013; Valdez et al., 2012). 1,5-Diarylpentanoid dibenzylideneacetone (DBA) and their derivatives are compounds that have an acyclic dienone attached to aryl groups in both β-positions. These compounds have demonstrated antiproliferative, anti-inflammatory and apoptotic effects in cancer cell lines (Bhandarkar et al., 2008; Prasad et al., 2011; Ud Din et al., 2014; Yu et al., 2013). Others studies have reported the anti-leishmanial and anti-trypanosomal effects of the DBAs derivatives (Garcia et al., 2017; Lazarin-Bidóia et al., 2016). Considering that the available chemotherapy is inefficient for patients, research is a need in search of new therapies (Wilkinson and Kelly, 2009). Based on the context, the aim of this study is to elucidate the activity and the main alterations induced by dibenzylidenoacetone derivate (E)−3-ethyl-4-(4-nitrophenyl)but-3-en-2-one (A11K3) against epimastigotes, trypomastigotes and intracellular amastigotes of T. cruzi.
Section snippets
Chemicals
The following chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA): carbonyl cyanide m-chlorophenylhydrazone (CCCP), rhodamine 123 (Rh123), dansylcadaverine (MDC), Nile red, digitonin, methylphenazinium methyl sulfate (PMS), dihydrochlorofluorescein (H2DCFDA), wortmannin, potassium cyanate (KCN) and dimethyl sulfoxide (DMSO). LIT (liver infusion yeast extract), hemin and folic acid were acquired from Sigma-Aldrich (St. Louis, MO, USA). The
Preparation of the derivate A11K3
The reaction of p-nitrobenzaldehyde (A11) with 2-pentanone (K3), using gaseous HCl as a catalyst, as outlined in Fig. 2, was performed at room temperature by stirring the reaction mixture and passing the dry gaseous HCl over the reaction until the mixture turned white-yellow (Fig. 2).
Activity of A11K3 against T. cruzi epimastigotes, trypomastigotes and intracellular amastigotes
In the present study, we analyzed the activity of a dibenzylideneacetone, A11K3, against the three developmental forms of T. cruzi. The compound showed an IC50/96h of 3.3 ± 0.8 µM against epimastigotes, an EC50/24 h
Discussion
In our recent studies on the synthesis of curcumin analogues, or diaryalkadienones, we have performed many different reactions of aldehydes (An) with ketones (Km) in various conditions to produce the aldols intermediaries following its condensation on pot (Din et al., 2018). The reaction of p-nitrobenzaldehyde (A11) with 2-pentanone (K3) occurs via the thermodynamic enolate giving good regiochemistry control, yielding almost 100% of A11K3 without a detectable amount of aldol condensation via
Conclusion
This study with a DBA derivate A11K3 has demonstrated that the compound is efficient against epimastigotes, trypomastigotes and intracellular amastigotes of T. cruzi. The biochemical assays are performed with epimastigotes and intracellular amastigotes because are forms replicative of T. cruzi. In addition, the amastigotes are forms found during chronic phase of Chagas disease, collaborating for the next steps of the study with A11K3.
The results suggest that A11K3 has less toxic for mammalian
CRediT authorship contribution statement
Jéssica Carreira de Paula: Conceptualization, Data curation, Formal analysis, Methodology, Investigation, Writing - original draft. Amanda Beatriz Kawano Bakoshi: Validation, Visualization, Methodology, Writing - review & editing. Danielle Lazarin-Bidóia: Validation, Visualization, Methodology, Writing - review & editing. Zia Ud Din: Methodology, Validation. Edson Rodrigues-Filho: Methodology, Validation. Tania Ueda-Nakamura: Funding acquisition, Project administration, Supervision, Writing -
Declaration of Competing Interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by the Coordination of Improvement of Higher Level Personnel (Capes – Brazil), National Council for Scientific and Technological Development and Sciences without Borders Program (CNPq – Brazil), Araucaria Foundation (Brazil), Financier of Studies and Projects (Finep - Brazil) and COMCAP – UEM. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.
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