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

• Lysine deacetylases inhibitors effects need to be investigated on the parasite. • 4-[(10H-phenothiazine-10-yl)methyl]-N-hydroxybenzamide (KV-46) was used in the study. • KV-46 altered parasite proliferation and viability, promoting cytokinesis arrest. • Ultrastructural changes like autophagy were observed on treated cells. • KV-46 is promising for developing a new drug for giardiasis treatment. Giardiasis is an intestinal disease caused by the parasite protozoan Giardia intestinalis. For more than five decades, the treatment of this disease has been based on compounds such as nitroimidazoles and benzimidazoles. The parasite's adverse effects and therapeutic failure are largely recognized. Therefore, it is necessary to develop new forms of chemotherapy treatment against giardiasis. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins as tubulin, are found in the Giardia genome and can become an interesting option for giardiasis treatment. In the present study, we evaluated the effects of 4-[(10 H -phenothiazin-10-yl)methyl]-N-hydroxybenzamide, a new class I/II KDAC inhibitor, on G. intestinalis growth, cytoskeleton, and ultrastructure organization. This compound decreased parasite proliferation and viability and displayed an IC 50 value of 179 nM. Scanning electron microscopy revealed the presence of protrusions on the cell surface after treatment. In addition, the vacuoles containing concentric membranous lamella and glycogen granules were observed in treated trophozoites. The cell membrane appeared deformed just above these vacuoles. Alterations on the microtubular cytoskeleton of the parasite were not observed after drug exposure. The number of diving cells with incomplete cytokinesis increased after treatment, indicating that the compound can interfere in the late steps of cell division. Our results indicate that 4-[(10 H -phenothiazin-10-yl)methyl]-N-hydroxybenzamide should be explored to develop new therapeutic compounds for treating giardiasis. 4-[(10 H -phenothiazin-10-yl)methyl]-N-hydroxybenzamide, a lysine deacetylases inhibitor, alters G. intestinalis proliferation and viability, induces arrest in the cytokinesis stage, and led to changes on ultrastructure organization. [Display omitted] [ABSTRACT FROM AUTHOR]