Potencial ação anti-Toxoplasma gondii de dois novos compostos químicos sintéticos em modelos de interface materno-fetal humana

Abstract

The conventional treatment for congenital toxoplasmosis primarily relies on a combination of sulfadiazine and pyrimethamine. However, therapy with these drugs is associated with severe side effects and resistance, necessitating the exploration of new therapeutic strategies. Currently, studies are underway with chemical compounds, including those based on benzamidazole and pyridine derivates, demonstrating effective actions against several pathogens, including protozoans. In this particular study, we investigated the effects of two new compounds, namely RVI 30 and RVI 33, in BeWo cells and human third-trimester placental villi explants when infected with Toxoplasma gondii. For this purpose, BeWo cells and explants were infected or not with T. gondii, treated with RVI 30 or RVI 33 and analyzed for toxicity, parasite adhesion, invasion and proliferation, as well as cytokine production. Additionally, BeWo cells were infected with RVIs-pretreated tachyzoites and we observed invasion rate. Finally, the tachyzoites were observed regarding to ultrastructural changes when treated with both compounds. Our results showed that both compounds did not induce toxicity at low concentrations and were capable of reducing T. gondii intracellular proliferation in previously infected cells. Furthermore, they demonstrated irreversible antiparasitic action in BeWo cells. Subsequently, T. gondii invasion was attenuated when BeWo cells were infected with pretreated tachyzoites. Finally, infected BeWo cells treated with RVI 30 and RVI 33 upregulated MIF and decreased IL-8 when treated only with RVI 30. Moreover, the compounds reduced T. gondii proliferation in human explants, with no significant changes in cytokine production. Finally, important changes were detected in the parasite morphology when BeWo cells were treated with both compounds. In summary, RVI 30 and RVI 33 exhibited different antiparasitic activities depending on the experimental model, highlighting direct action on tachyzoites as a common mechanism in both cells and villi. Based on these findings, RVI 30 and RVI 33 are suggested as promising targets for the establishment of new therapeutic strategies against congenital toxoplasmosis.