In this work, we described the investigation of three new HDAC inhibitor chemotypes derived from the core scaffold of the anticancer drug candidate quisinostat. Our multicomponent synthesis approach enabled the discovery of novel, highly active HDAC inhibitors with substantially reduced cytotoxicity against non-cancer cells (MRC-5 cells) compared to quisinostat. The most active antiplasmodial compound turned out to be 18b with low double-digit nanomolar activity against Pf3D7 and PfDd2 strains. Different binding modes of 18b with P. falciparum and human HDAC1 were suggested by docking studies. Interestingly, the type C scaffold exposed low cytotoxicity against MRC-5 cells but potent antiplasmodial activity, making it an interesting scaffold for antimalarial HDAC inhibitor drug discovery. We also assessed the inhibitory potential against human HDAC1 and HDAC6 and found that most compounds showed potent and preferential inhibitory activity against HDAC1. Additionally, we demonstrated that 18b is able to inhibit the supposed main target of our antiplasmodial HDAC inhibitors,