The rational development of selective antiplasmodial HDAC inhibitors remains challenging. The previously reported high antiplasmodial activity of quisinostat derivatives built a foundation for a new antiplasmodial HDAC inhibitor chemotype. Nevertheless, quisinostat is highly toxic as we showed in MRC-5 cells (IC50 = 0.044 µM) and therefore not suitable for the treatment of diseases beyond cancer. With our approach of multicomponent synthesis-driven development of quisinostat analogs, a diverse set of compounds could be generated and screened for antiplasmodial activity and cytotoxicity with the aim of identifying selective antiplasmodial HDAC inhibitors. Many compounds of the types A and B also showed high toxicity in the single-digit micromolar range (9a-d and 13d-f).