Toxicity and Loss of Mitochondrial Membrane Potential Induced by Alkyl Gallates in <i>Trypanosoma cruzi</i>

Andréo, Rogério; Regasini, Luís Octávio; Petrônio, Maicon Segalla; Chiari-Andréo, Bruna Galdorfini; Tansini, Aline; Silva, Dulce Helena Siqueira da; Cicarelli, Regina Maria Barretto

doi:10.1155/2015/924670

Cited by 10 publications

(11 citation statements)

References 47 publications

(47 reference statements)

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“…The trypanocidal activity of gallic acid could be due to the presence of the extra hydroxyl group and its ability to form reactive oxygen intermediates in the parasite [19]. Although gallic acid showed trypanocidal activity in this study, interestingly, in other studies, gallic acid was inactive against other kinetoplastids such as Leishmania donovani and Trypanosoma cruzi [19, 20] and this could be due to the intracellular nature of these parasites. The amastigote forms of Leishmania and the amastigotes of Trypanosoma cruzi exists intracellularly in mammalian cells.…”

Section: Discussionmentioning

confidence: 62%

“…A fully functional mitochondrion will have an intact membrane potential leading to the internalization and the retention of the dye in the mitochondrion. In a defective or leaky mitochondrion, the membrane potential will be lost, and the dye will aggregate in the cytoplasm [20]. The generation of reactive oxygen species causes damage to the mitochondrion leading to a loss in its membrane potential [25].…”

Section: Discussionmentioning

confidence: 99%

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In vitro anti-trypanosomal effects of selected phenolic acids on Trypanosoma brucei

et al. 2019

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African trypanosomiasis remains a lethal disease to both humans and livestock. The disease persists due to limited drug availability, toxicity and drug resistance, hence the need for a better understanding of the parasite’s biology and provision of alternative forms of therapy. In this study, the in vitro effects of phenolic acids were assessed for their trypanocidal activities against Trypanosoma brucei brucei . The effect of the phenolic acids on Trypanosoma brucei brucei was determined by the alamarBlue assay. The cell cycle effects were determined by flow cytometry and parasite morphological analysis was done by microscopy. Effect on cell proliferation was determined by growth kinetic analysis. Reverse Transcriptase quantitative Polymerase Chain Reaction was used to determine expression of iron dependent enzymes and iron distribution determined by atomic absorption spectroscopy. Gallic acid gave an IC 50 of 14.2±1.5 μM. Deferoxamine, gallic acid and diminazene aceturate showed a dose dependent effect on the cell viability and the mitochondrion membrane integrity. Gallic acid, deferoxamine and diminazene aceturate caused loss of kinetoplast in 22%, 26% and 82% of trypanosomes respectively and less than 10% increase in the number of trypanosomes in S phase was observed. Gallic acid caused a 0.6 fold decrease, 50 fold increase and 7 fold increase in the expression levels of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes respectively while treatment with deferoxamine and diminazene aceturate also showed differential expressions of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes. The data suggests that gallic acid possibly exerts its effect on T . brucei via iron chelation leading to structural and morphological changes and arrest of the cell cycle. These together provide information on the cell biology of the parasite under iron starved conditions and provide leads into alternative therapeutic approaches in the treatment of African trypanosomiasis.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

In vitro anti-trypanosomal effects of selected phenolic acids on Trypanosoma brucei

et al. 2019

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“…Based on our proposition, Gly 2 treatment lead to repudiation of promastigotes further causing increased ROS generation whereas control parasites showed balanced redox homeostasis. Further, it has been reported that drug-induced loss in ∆Ψm is associated with cellular death in L. donovani, L. amazonensis and Trypanosoma cruzi [44]. ∆Ψm loss and ROS elevation are coupled events and act as crucial signals of necrosis [45].…”

Section: Discussionmentioning

confidence: 99%

Metalloprotease Gp63 targeting novel glycoside exhibits potential antileishmanial activity

Chakrabarti

Narayana

Joshi

et al. 2020

Preprint

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Visceral Leishmaniasis (VL) and its aggressive cutaneous exacerbation known as Post Kala-azar Dermal Leishmaniasis (PKDL) cause a huge disease burden in tropics and sub-tropic endemic zones worldwide. Contemporary treatment modalities have been associated with various complications. Encouraged from the recent marked antimalarial effects from plant derived glycosides; here we have chemically synthesized a library of diverse Glycoside derivatives (Gly 1-12) and evaluated their inhibitory efficacy against Ag83 strain of Leishmania donovani. In vitro activity of Glycoside-2 (Gly 2) on Ag83 strain, unravelled its prominent anti-leishmanial property with IC50 value of 1.13μM. In-silico studies also unveiled the efficacy of Gly 2 to bind to the membrane surface of parasite. The toxic effect of Gly 2 causes necrosis like death in promastigote by abrogating its proliferation leading to imbalanced redox homeostasis by disruption of mitochondrial membrane potential. Additionally, Gly 2 treatment demonstrated increased susceptibility of parasites towards complement mediated lysis and displayed strong lethal effect on amastigote-macrophage infection model mimicking pathophysiological condition of body. This lead molecule was quite effective against the clinical PKDL strain BS12 with IC50 value of 1.97 μM making it the most suitable drug so far which can target both VL and PKDL simultaneously. Based on the above experimental validations we narrowed our thoughts regarding the potent role of Gly 2 targeting surface protein of L. donovani such as Gp63, a zinc metalloprotease. Further analysis of structure activity relationship (SAR) of these glycoside derivatives, demonstrated exceptional binding affinity of Gly 2 towards Gp63, a zinc metalloprotease of L. donovani; with strong H-bond interactions of Gly 2 with catalytic domain in the α-helix B region of Gp63. The strong confined interactions between Gly 2 and the target protein Gp63 in a physiologically relevant cellular environment was further assessed by Cellular Thermal Shift Assay (CETSA) which corroborated with our previous results. Taken together, this study reports the serendipitous discovery of glycoside derivative Gly 2 with enhanced leishmanicidal activity and proves to be novel chemotherapeutic prototype against VL and PKDL.

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“…Anti-pathogenic activity of alkyl gallates has been investigated in another eukaryote Trypanosoma cruzi, a causative agent of Chagas disease (Andréo et al, 2015). Results showed that longer-chain alkyl gallates, viz., nonyl, decyl, undecyl, dodecyl gallates, exhibited potent anti-trypanosomal activity, where loss of mitochondrial potential in T. cruzi could be one mechanism of anti-trypanosomal action of alkyl gallates (Andréo et al, 2015).…”

Section: Introduction (Continued)mentioning

confidence: 99%

Repurposing Common Food Additives (Benzo Derivatives) As New Anti-parasitic Agents

Land

Kim

Huang

et al. 2019

Proceedings of 5th International Electronic Conference on Medicinal Chemistry

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This study examined the anti-protozoal effects of selected benzo derivatives, namely ten gallic acid (GA) alkyl esters (viz., benzoic acid analogs) and twenty-three benzaldehyde analogs, against six different anaerobic human protozoal pathogens-Trichomonas vaginalis, Tritrichomonas foetus, Tritrichomonas foetus-like, Giardia lamblia, Entamoeba histolytica, and Naegleria fowleri. The efficacy of benzaldehyde and gallate (3,4,5-trihydroxybenzoic acid) analogs were investigated in two respects: (1) changing types of side chains and their positions on the benzaldehyde ring [structure-activity relationships (SAR)]; and, (2) changing lengths of alkyl chains esterified with the carboxyl group on gallate. Results of parasite growth inhibition assays indicated that benzo derivatives could be further developed as potent anti-protozoal drug candidates/leads, where GA having longer alkyl chains exhibited higher anti-protozoal activity than compounds with shorter alkyl chains or all benzaldehyde analogs tested. The chemical libraries were also screened against common human microbiome bacteria and no detectable inhibition was observed. Structure-activity relationships and their implications for new drug discovery against these sexually-transmitted, water-borne, and foodborne parasites are discussed.

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Toxicity and Loss of Mitochondrial Membrane Potential Induced by Alkyl Gallates in Trypanosoma cruzi

Cited by 10 publications

References 47 publications

In vitro anti-trypanosomal effects of selected phenolic acids on Trypanosoma brucei

In vitro anti-trypanosomal effects of selected phenolic acids on Trypanosoma brucei

Metalloprotease Gp63 targeting novel glycoside exhibits potential antileishmanial activity

Repurposing Common Food Additives (Benzo Derivatives) As New Anti-parasitic Agents

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