Repurposing 6‑Anilinopurine Derivatives That Exhibit PfHDAC1 Inhibition and Antimalarial Activity against Asexual and Sexual Stages of Plasmodium falciparum.

Malaria is a disease caused by protozoans of the genus Plasmodium that claims hundreds of thousands of lives each year. The emergence of resistant strains to the currently available antimalarials urges the need to find novel compounds capable of impairing the development or transmission of the parasites. Histone deacetylase (HDAC) inhibitors are a class of compounds largely explored in antineoplastic therapy, often acting as effective and specific tumor-targeted drugs. In this work, we investigated the antimalarial activity of 6-Anilinopurine derivatives originally developed for their anticancer chemotherapeutic properties. Our results show that the compounds exhibit nanomolar activity against the asexual stages of Plasmodium falciparum wild-type and chloroquine-resistant strains in vitro. Moreover, 13 out of 14 compounds tested showed gametocidal activity after 48 h treatment, indicating their ability to inhibit the transmission of parasites from the human host to the mosquito vector. The activity of these compounds is attributed to the inhibition of P. falciparum HDAC1, an important enzyme in the parasite's development. These results highlight that repurposing the use of HDAC inhibitors has significant potential in antimalarial therapy.