Synthesis of Xylitan Derivatives and Preliminary Evaluation of in Vitro Trypanocidal Activity

Elias, Paula Regina; Coelho, Gleicekelly Silva; Xavier, Viviane Flores; Sales, Policarpo Ademar; Romanha, Álvaro J.; Murta, Silvane Maria Fonseca; Carneiro, Cláudia Martins; Camilo, Nilton Soares; Hilário, Flaviane Francisco; Taylor, Jason G.

doi:10.3390/molecules21101342

Cited by 13 publications

(9 citation statements)

References 22 publications

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Section: T Cruzi Activitymentioning

confidence: 99%

“…The use of the epimastigote form present in the midgut vector can be employed for an in vitro screening method (Menezes et al, 2014;Moreira et al, 2014) but we have opted for a methodology that simultaneously evaluates trypomastigote forms that are initially present in the blood after entering through the bite wound and intracellular amastigotes forms present in the vertebrate host during the acute and chronic phases of the disease (de Souza et al, 2018;Elias et al, 2016). This approach is in accordance with the guidelines proposed by the Fiocruz Program for Research and Technological Development on Chagas Disease and the Drugs for Neglected Diseases Initiative (DNDi) (de Souza et al, 2018;Elias et al, 2016). Furthermore, the whole cell-based screening methodology is also attractive given that bioactive compounds can be tested for anti-T. cruzi activity in infected cells while at the same time monitoring their effects on both amastigotes and trypomastigotes in the same system.…”

Section: T Cruzi Activitymentioning

confidence: 99%

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Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

et al. 2018

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Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side‐effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti‐T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays.

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Section: T Cruzi Activitymentioning

confidence: 99%

Section: T Cruzi Activitymentioning

confidence: 99%

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

et al. 2018

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“…[12][13][14] Following the guidelines proposed by the Fiocruz Program for Research and Technological Development on Chagas Disease Initiative, the whole cell-based screening methodology was utilized in the present study. 15,16 This allows us to study the parasite forms that are responsible for human infection, analyse novel compounds for anti T. cruzi activity in infected cells whilst at the same time monitoring their effects on amastigotes and trypomastigotes in the same system. Different azole derivatives such as imidazoles, 9,17 thiazoles, 12,18 1,3,4-oxadiazoles, 19 1,2,4-oxadiazoles 20 and 1,2,3-triazoles 21 have been evaluated for their anti T. cruzi activity (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3,5-Diarylisoxazole Derivatives and Evaluation of in vitro Trypanocidal Activity

Souza¹,

Xavier²,

Coelho³

et al. 2017

J. Braz. Chem. Soc.

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Chagas disease is included in the neglected tropical diseases list and is endemic to 21 Latin American countries. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole and both result in many significant side effects. The study describes the synthesis and biological evaluation of 3,5-disubstituted isoxazoles. Isoxazoles were obtained by reaction of flavones and hydroxylamine and either alkylated at the free hydroxyl group and/or nitrated at the isoxazole ring. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as a reference compound for the in vitro assay and mammalian L929 cells were employed to evaluate cytotoxicity. A majority of the compounds tested were very active and the most active isoxazole against amastigote and trypomastigotes of T. cruzi was slightly more potent than the current medicine benznidazole.

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“…We have opted for an in vitro methodology that simultaneously evaluates trypomastigote forms that are initially present in the blood after entering through the bite wound and intracellular amastigotes forms present in the vertebrate host during the acute and chronic phases of the disease. 16 This approach is in accordance with the guidelines proposed by the Fiocruz Program for Research and Technological Development on Chagas Disease and the Drugs for Neglected Diseases Initiative (DNDi). 17 Benznidazole was used as a positive control against T. cruzi and cytotoxicity was determined in mammalian L929 cells (Table 1).…”

Section: Resultsmentioning

confidence: 95%

In Vitro Evaluation of Synthetic Flavones Against Trypanosoma cruzi

Andrade

Abreu²,

Sales³

et al. 2021

Rev. Virtual Quim.

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Resumo: A doença de Chagas é uma infeção causada pelo protozoário parasita Trypanosoma cruzi e afeta cerca de 8 milhões de pessoas em 21 países da América Latina. O tratamento dessa doença ainda se baseia no uso de benzonidazol ou nifurtimox, que apresentam baixas taxas de cura na fase crônica e frequentemente apresentam muitos efeitos colaterais indesejáveis. Aqui, descrevemos a síntese de flavonas e a avaliação de sua atividade tripanocida. As flavonas foram testadas in vitro contra o T. cruzi e dentre os 13 compostos testados, 6 destes demonstraram alguma atividade tripanocida modesta in vitro. Observaram-se melhorias na atividade anti T. cruzi para flavonas portadoras de substituintes nitro ou metóxi. Notavelmente, foram mantidas citotoxicidades muito baixas com grupos metoxila, o que sugere que esse grupo funcional favorece compostos tripanocidas mais seletivos. Além disso, a modificação estrutural na posição 3 do anel diidropirona forneceu a flavona mais ativa, o que sugere que a introdução de diferentes funcionalidades nessa posição poderia gerar novos compostos promissores com propriedades tripanocidas. Chagas disease is caused by infection of the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. Treatment of this disease is still based on the use of benznidazole or nifurtimox, which both present low cure rates in the chronic phase and often have many undesirable side effects. Herein, we describe the synthesis of flavones and evaluation of their trypanocidal activity. The flavones were tested to in vitro against T. cruzi and amongst the 13 compounds tested, 6 of these demonstrated some modest trypanocidal activity in vitro. Enhancements in anti T. cruzi activity were noted for flavones bearing either nitro or methoxy substituents. Moreover, very low cytotoxicities were maintained for flavones with methoxy groups which suggests that this functional group favors more selective trypanocidal compounds. Finally, structural modification at position 3 of the dihydropyrone ring provided the most active flavone, which suggests that the introduction of different functionalities at this position could yield promising new compounds with trypanocidal properties.

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Synthesis of Xylitan Derivatives and Preliminary Evaluation of in Vitro Trypanocidal Activity

Cited by 13 publications

References 22 publications

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

Synthesis of 3,5-Diarylisoxazole Derivatives and Evaluation of in vitro Trypanocidal Activity

In Vitro Evaluation of Synthetic Flavones Against Trypanosoma cruzi

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