trans-Chalcone modulates Leishmania amazonensis infection in vitro by Nrf2 overexpression affecting iron availability

Miranda-Sapla, Milena Menegazzo; Tomiotto-Pellissier, Fernanda; Assolini, João Paulo; Carloto, Amanda Cristina Machado; Bortoleti, Bruna Taciane da Silva; Gonçalves, Manoela Daiele; Tavares, Eliandro Reis; Rodrigues, Jean Henrique da Silva; Simão, Andréa Name Colado; Yamauchi, Lucy Megumi; Verri, Waldiceu A.; Costa, Idessânia Nazareth; Conchon‐Costa, Ivete; Pavanelli, Wander Rogério

doi:10.1016/j.ejphar.2019.03.049

Cited by 40 publications

(18 citation statements)

References 64 publications

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“…Despite discussion regarding the occurrence of PS exposure in the external leaflet of the Leishmania plasma membrane, since there is a possibility of this phospholipid being absent or present in small amounts in this parasite membrane (Proto et al, 2013), the labeling of this phospholipid with annexin V-FITC has been widely used to detect an apoptosis-like process in Leishmania (Mesquita et al, 2013;Chouhan et al, 2015;Mallick et al, 2015;Bortoleti et al, 2018;Gonçalves et al, 2018;Tomiotto-Pellissier et al, 2018;Miranda-Sapla et al, 2019). In this work, this probe was used to evaluate the PS externalization in L. infantum promastigotes after treatment with PF-429242.…”

Section: The Killing Induced By Pf-429242 In L Infantum Promastigotes Seems To Be Unrelated To Apoptosis-like And/or Necrosismentioning

confidence: 99%

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

et al. 2021

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PF-429242 is an inhibitor of subtilisin, an important protease found in Leishmania. However, studies regarding the effect of PF-429242 on Leishmania are scarce. In this work we evaluated the antileishmanial effect of PF-429242 against Leishmania infantum and the mechanism involved in the death of the parasite. PF-429242 had low toxicity against mammalian cells (peritoneal macrophages) (CC50 = 189.07 μM) and presented activity against L. infantum promastigotes (IC50 = 2.78 μM) and intracellular amastigotes (IC50 = 14.07 μM), indicating selectivity toward the parasite. Transmission electron microscopy (TEM), as well as staining of L. infantum promastigotes with MitoTracker® Red, rhodamine 123 and MitoSOX, revealed that the mitochondria was a potential target of PF-429242. In addition, PF-429242 caused an accumulation of neutral lipids in promastigotes, which was demonstrated by Nile Red staining and TEM, and induced oxidative stress (H2DCFDA staining). Furthermore the formation of autophagic vacuoles in L. infantum promastigotes was observed by MDC staining and TEM. However, the killing induced by PF-429242 in L. infantum promastigotes appeared to be unrelated to apoptosis and/or necrosis as there was no phosphatidylserine externalization, DNA fragmentation or alterations in the permeability of the parasite plasma membrane, as assessed by annexin V-FITC, TUNEL and propidium iodide staining, respectively. The morphological and ultrastructural evaluation of the promastigotes by optical microscopy, scanning electron microscopy (SEM) and TEM, revealed the presence of parasites with flagellar defects. TEM analysis of the intracellular amastigotes indicated that mitochondrial damage and autophagy could also be involved in the death of these forms after treatment with PF-429242. In addition, PF-429242 treatment stimulated NO production from infected macrophage, but only at a high concentration (100 μM), as well as an increase of TNF levels after treatment with 10 μM of PF-429242. The compound did not stimulate ROS or IL-10 production. Together, these data highlight the antileishmanial potential of PF-429242, inducing several cellular alterations in the parasite, such as mitochondrial damage, neutral lipids accumulation, oxidative stress and autophagy which culminate in the death of L. infantum, as well as modulating host cellular responses that favor the development of an immune response against the parasite.

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Section: The Killing Induced By Pf-429242 In L Infantum Promastigotes Seems To Be Unrelated To Apoptosis-like And/or Necrosismentioning

confidence: 99%

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

et al. 2021

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“…The early efforts to overcome these limitations were directed to the improvement of the drug delivery systems , and the formulation of more effective combination therapies . However, the cost increase − and the rapid recurrence of resistance phenomena − prompted the scientific community to turn its attention toward the development of new antileishmanial drugs, − which should be effective, safe, and not expensive. Concerning the research and development of new improved drugs, four main approaches are exploited: (i) drug repurposing, as in the case of fexinidazole (Figure ); (ii) diversity-oriented screening of collections of chemicals, such as oxaborole AN-4169 , and aminopyrazole amide 1 (Figure ); (iii) phenotypic screening, leading to the identification of new biological targets and effective inhibitors, − such as 17-AAG (HSP90 inhibitor) (Figure ); and (iv) use of known or new natural products with limited side effects, − especially those deriving from plants, such as fucoidan and 11,13-dehydrocompressanolide (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

et al. 2020

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Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro , and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania .

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“…The generic structure of chalcones is known for the electron-donating tendency characteristic of the ketoethylene bridge between the A and B rings 73 and, in the results, it is possible to observe the strong contribution that this unit has in binding with biological macromolecules such as DNA. This parameter emphasizes the toxicological predictions from in silico studies, since it is associated with structural contributions to Ames mutagenicity.…”

Section: Resultsmentioning

confidence: 99%

Quantum mechanical, molecular docking, molecular dynamics, ADMET and antiproliferative activity onTrypanosoma cruzi(Y strain) of chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one derived from a natural product

Matos

Silva

Almeida-Neto

et al. 2022

Phys. Chem. Chem. Phys.

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trans-Chalcone modulates Leishmania amazonensis infection in vitro by Nrf2 overexpression affecting iron availability

Cited by 40 publications

References 64 publications

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

Quantum mechanical, molecular docking, molecular dynamics, ADMET and antiproliferative activity onTrypanosoma cruzi(Y strain) of chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one derived from a natural product

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