In vitro effects of the 4-[(10H-phenothiazin-10-yl)methyl]-N-hydroxybenzamide on Giardia intestinalis trophozoites

Oliveira, Roberta Veríssimo F.; Souza, Wanderley de; Vögerl, Katharina; Bracher, Franz; Benchimol, Marlene; Gadelha, Ana Paula Rocha

doi:10.1016/j.actatropica.2022.106484

Cited by 5 publications

(2 citation statements)

References 54 publications

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“…For example, Benchimol and coworkers (2022) described Giardia shape changes and the presence of large vesicles when it ingested macromolecules via receptor-mediated endocytosis, and they mentioned that these large vesicles might represent a new organelle [ 33 ]. Recently, Roberta Veríssimo and collaborators (2022) showed the presence of large protrusions in the membrane due to the effect of 4-((10H-phenothiazine-10-yl)methyl)ppaa-N-hydroxybenzamide using TEM, and they demonstrated that these protrusions corresponded to large vacuoles that harbored lamellar bodies, glycogen granules, ribosomes, and some internalized flagella, indicating that the cell may be undergoing programmed cell death similar to autophagy [ 34 ]. Conversely, a previous work with lactoferrin by Hugo Aguilar-Diaz and collaborators (2017) showed the presence of blisters and perforations in the plasma membrane of Giardia with unusual aggregates, suggesting that Giardia could be undergoing programmed cell death damage [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Terfenadine as a Novel Antigiardial Compound

Suárez-Rico,

Munguía-Huizar,

Cortés-Zárate

et al. 2023

Pharmaceuticals

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Giardia lamblia is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for giardiasis treatment have limitations such as side effects and drug resistance, requiring the search for new antigiardial compounds. Drug repurposing has emerged as a promising strategy to expedite the drug development process. In this study, we evaluated the cytotoxic effect of terfenadine on Giardia lamblia trophozoites. Our results showed that terfenadine inhibited the growth and cell viability of Giardia trophozoites in a time–dose-dependent manner. In addition, using scanning electron microscopy, we identified morphological damage; interestingly, an increased number of protrusions on membranes and tubulin dysregulation with concomitant dysregulation of Giardia GiK were observed. Importantly, terfenadine showed low toxicity for Caco-2 cells, a human intestinal cell line. These findings highlight the potential of terfenadine as a repurposed drug for the treatment of giardiasis and warrant further investigation to elucidate its precise mechanism of action and evaluate its efficacy in future research.

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Section: Discussionmentioning

confidence: 99%

Repurposing Terfenadine as a Novel Antigiardial Compound

Suárez-Rico,

Munguía-Huizar,

Cortés-Zárate

et al. 2023

Pharmaceuticals

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“…Additionally, novel HDAC inhibitors named KH-TFMDI, a member of the 3-arylideneindolin-2-one family, and KV-46, a 4-[(10H-phenothiazin-10-yl)methyl]-N-hydroxy benzamide, exhibited the ability to modulate G. intestinalis growth, with IC50 values below 1 μM ( Figure 17 ). Moreover, these compounds induced cytokinesis arrest and the formation of vacuoles with autophagic characteristics [ 67 , 86 ]. Although the primary mechanism of action for these compounds involves the inhibition of histone deacetylases, it is possible that they also impact other parasite pathways.…”

Section: Potential Drug Targetmentioning

confidence: 99%

Ultrastructural Alterations of the Human Pathogen Giardia intestinalis after Drug Treatment

2023

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This review presents the main cell characteristics altered after in vitro incubation of the parasite with commercial drugs used to treat the disease caused by Giardia intestinalis. This important intestinal parasite primarily causes diarrhea in children. Metronidazole and albendazole are the primary compounds used in therapy against Giardia intestinalis. However, they provoke significant side effects, and some strains have developed resistance to metronidazole. Benzimidazole carbamates, such as albendazole and mebendazole, have shown the best activity against Giardia. Despite their in vitro efficacy, clinical treatment with benzimidazoles has yielded conflicting results, demonstrating lower cure rates. Recently, nitazoxanide has been suggested as an alternative to these drugs. Therefore, to enhance the quality of chemotherapy against this parasite, it is important to invest in developing other compounds that can interfere with key steps of metabolic pathways or cell structures and organelles. For example, Giardia exhibits a unique cell structure called the ventral disc, which is crucial for host adhesion and pathogenicity. Thus, drugs that can disrupt the adhesion process hold promise for future therapy against Giardia. Additionally, this review discusses new drugs and strategies that can be employed, as well as suggestions for developing novel drugs to control the infection caused by this parasite.

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