CONICET | Buscador de Institutos y Recursos Humanos

Neglected tropical diseases (NTDs) caused by cestodes, such as echinococcosis and cysticercosis, represent a serious public health problem in many countries; including Argentine. These diseases have a reduced number of safe and efficacious approved anthelmintic drugs; therefore, the identification of novel drug candidates is urgently required. In this work, we present the anthelmintic profile of several series of recently developed selective histone deacetylase (HDAC) inhibitors (benzhydroxamate derivatives) against the isotype 8, using the model cestode Mesocestoides vogae (syn. M. corti). Phenotypic screenings were performed measuring parasite motility together with optical microscope observations. Several compounds showed potent anthelmintic activities, producing a significant reduction on parasite viability and inducing extensive alterations on general morphology. Two of these compounds, TH65 and TH92, showed the most powerful anthelmintic effects, displaying anthelmintic effects in a dose-dependent manner, with micromolar range activities, and inducing drastic alterations on general morphology and ultrastructural features. These effects were irreversible and with higher potencies than the current anthelmintic drug albendazole. Additionally, binary combinations of HDAC8 inhibitors and albendazole showed potent anthelmintic effects in a time-dependent manner at very low concentrations, suggesting an apparent synergistic effect. However, the effects determined for some compounds were not comparable in concentration and/or incubation time to those previously reported on Schistosoma mansoni viability and human cell lines, suggesting differences in the affinity for HDAC8 from M. vogae compared to other HDAC8s. We expect that this work contributes to understand the role of HDAC enzymes on cestodes, in order to aid in developing of new anti-parasitic treatments against NTDs caused by these parasites.