Multicomponent Syntheses Enable the Discovery of Novel Quisinostat-Derived Chemotypes as Histone Deacetylase Inhibitors

Epigenetic drug targets have become an important focus in drug discovery. One of the key mechanisms in epigenetics is the acetylation and deacetylation of histone proteins. In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. The compounds were evaluated for their activity against Plasmodium falciparum, the main malaria parasite, and solid cancer cell lines. The antiplasmodial activity was assessed against P. falciparum strains 3D7 and Dd2, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 µM; IC50 (Dd2) = 0.047 µM) and high parasite selectivity (SIMRC-5/Pf3D7 > 2174). Docking studies suggested distinct binding modes of 18b with P. falciparum and human HDAC1. The in vitro anticancer activity was also evaluated in the Cal27 and HepG2 cell lines and compounds 9b, 9d, and 13f showed potent antiproliferative activity. Compound 9d significantly induced caspase 3/7-mediated apoptosis and caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified several promising HDAC inhibitors with antimalarial and anticancer activities, providing valuable leads for further drug development efforts aimed at creating derivatives with reduced cytotoxicity compared to quisinostat.