Chloride substitution on 2-hydroxy-3,4,6-trimethoxyphenylchalcones improves in vitro selectivity on Trypanosoma cruzi strain Y

Magalhães, Emanuel Paula; Gomes, Naiara Dutra Barroso; Freitas, Tiago Araújo de; Silva, Brenna Pinheiro; Ribeiro, Lyanna Rodrigues; Ameida-Neto, Francisco Wagner Queiroz; Marinho, Márcia Machado; Lima‐Neto, Pedro de; Marinho, Emmanuel Silva; Santos, Hélcio Silva dos; Teixeira, Alexandre Magno Rodrigues; Sampaio, Tiago Lima; Menezes, Ramon Róseo Paula Pessoa Bezerra de; Martins, Alice Maria Costa

doi:10.1016/j.cbi.2022.109920

Cited by 11 publications

(8 citation statements)

References 89 publications

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“…In the context of the natural products’ mode of action, oxidative stress figures as one of the most recurrent processes directly involved in their biological effect. The increase in ROS production as a result of chalcones treatment was already reported in trypanosomatids [ 22 , 23 , 24 , 40 ]. Here, the compound NaF at IC 50 /24 h concentration induced a remarkable increase in ROS levels in P. serpens promastigotes, similar to that previously observed in T. cru z i and L. amazonensis treated with other plant secondary metabolites, sesquiterpenoids and flavonoids , respectively [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 67%

“…Michael addiction involving chalcone derivative and glutathione thiols have already being reported in human cancer cells, resulting in GSH depletion and ROS elevation [ 51 , 52 ]. Furthermore, recent in vitro and in silico studies suggest that chalcones are able to bind in crucial sites of trypanothione reductase (TR) and tryparedoxin peroxidase (TXNPx), affecting their activity which leads to increased ROS levels [ 22 , 23 , 24 , 40 ]. Thus, ROS accumulation observed in P. serpens after the treatment with the chalcone NaF could be derived from the parasite’s redox unbalance, rather than causing a secondary mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, chalcone (1,3-diaryl-2-propane-1-one), a phenolic precursor made up of an α β-unsaturated carbonyl system that joins two aromatic rings [ 16 ], and its derivatives have stood out [ 17 , 18 , 19 , 20 , 21 ]. The inhibitory activity of a large amount of chalcone derivatives has already been well-described against Leishmania , T. cruzi and T. brucei [ 22 , 23 , 24 ]. In these parasites, chalcones and its derivatives mainly affect the mitochondrion, causing structural alterations in this organelle, as well as cytoplasmic and nuclear changes including vacuolization and DNA fragmentation [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

et al. 2023

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Phytomonas serpens is a trypanosomatid phytoparasite, found in a great variety of species, including tomato plants. It is a significant problem for agriculture, causing high economic loss. In order to reduce the vegetal infections, different strategies have been used. The biological activity of molecules obtained from natural sources has been widely investigated to treat trypanosomatids infections. Among these compounds, chalcones have been shown to have anti-parasitic and anti-inflammatory effects, being described as having a remarkable activity on trypanosomatids, especially in Leishmania species. Here, we evaluated the antiprotozoal activity of the chalcone derivative (NaF) on P. serpens promastigotes, while also assessing its mechanism of action. The results showed that treatment with the derivative NaF for 24 h promotes an important reduction in the parasite proliferation (IC50/24 h = 23.6 ± 4.6 µM). At IC50/24 h concentration, the compound induced an increase in reactive oxygen species (ROS) production and a shortening of the unique flagellum of the parasites. Electron microscopy evaluation reinforced the flagellar phenotype in treated promastigotes, and a dilated flagellar pocket was frequently observed. The treatment also promoted a prominent autophagic phenotype. An increased number of autophagosomes were detected, presenting different levels of cargo degradation, endoplasmic reticulum profiles surrounding different cellular structures, and the presence of concentric membranar structures inside the mitochondrion. Chalcone derivatives may present an opportunity to develop a treatment for the P. serpens infection, as they are easy to synthesize and are low in cost. In order to develop a new product, further studies are still necessary.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

et al. 2023

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“…These findings indicated that the chalcone-quinoline derivatives exert their antiparasitic activity through the inhibition of cruzipain [ 162 ]. The addition of chloride substituents to 2-hydroxy-3,4,6-trimethoxyphenylchalcones was shown to decrease the toxicity of the host cell against these compounds without impairing their inhibitory effects on the Trypanosoma cruzi Y strain forms [ 163 ]. The antiparasitic effect of chalcones and three of their amino analogs was evaluated against Trichomonas vaginalis , the causative agent of a non-viral illness known as Trichomoniasis, which is transmitted through sexual contact.…”

Section: Antiparasitic Activitymentioning

confidence: 99%

“… Inhibitory effects are associated with a rise in cytoplasmic ROS, mitochondrial malfunction, necrotic events, as well as the activity of TcTR and TcCr enzymes. [ 163 ] Chalcone and its amino analogs T. vaginalis In vitro, In vivo IC 50 : 29 μM; no toxicity against Galleria mellonella larvae. ROS accumulation in human neutrophils induced by trophozoites treated with aminochalcone 3.…”

Section: Antiparasitic Activitymentioning

confidence: 99%

Antiviral and antimicrobial applications of chalcones and their derivatives: From nature to greener synthesis

Nematollahi,

Mehrabani,

Hozhabri

et al. 2023

Heliyon

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Antitrypanosomal Potential of Chalcone‐Based Ursolic Acid Derivatives via Ligand‐Based Virtual Screening, DMPK Analyses, Molecular Dynamics Simulation, and MM/GBSA Binding Energy

Nunes,

da Rocha,

de de Oliveira

et al. 2024

ChemistrySelect

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Chagas disease, caused by the protozoan parasite Trypanosoma cruzi and transmitted mainly by triatomine insects, represents a significant challenge to public health, especially in impoverished regions. Current treatments, such as benznidazole and nifurtimox, have limitations, including serious side effects and reduced efficacy in the chronic phase. This work aims to evaluate the antitrypanosomal activity of ursolic acid‐derived chalcones (UACD) using a ligand‐based virtual screening approach. To this end, a series of independent molecular docking simulations were carried out (via AutoDock Vina code) with the parasite proliferation cycle enzymes TcGAPDH and cruzain. The most favorable candidates underwent drug metabolism and pharmacokinetics (DMPK) analyses and molecular dynamics (MD) simulations to estimate the pharmacokinetic and pharmacodynamic profile. Molecular docking simulations showed that the UACD derivatives showed better specificity for the TcGAPDH enzyme, emphasizing the ursolic acid and UACD3 derivatives (affinity energy = −9.4 kcal/mol for each). The DMPK prediction showed that the derivatives present viable apparent permeability (Papp) that promotes an excellent absorbed fraction (in 10⁻⁶ cm/s). MD simulations showed that the UACD3 derivative showed better free energy when binding to the TcGAPDH enzyme (−13.27 ± 1.87 kcal/mol) and interacting with the active site residues Cys166 and Thr167. However, both ligands appear to be alternative therapies in treating Chagas disease.

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Chloride substitution on 2-hydroxy-3,4,6-trimethoxyphenylchalcones improves in vitro selectivity on Trypanosoma cruzi strain Y

Cited by 11 publications

References 89 publications

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

Antiviral and antimicrobial applications of chalcones and their derivatives: From nature to greener synthesis

Antitrypanosomal Potential of Chalcone‐Based Ursolic Acid Derivatives via Ligand‐Based Virtual Screening, DMPK Analyses, Molecular Dynamics Simulation, and MM/GBSA Binding Energy

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