Discovery of Novel <i>Plasmodium falciparum</i> HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat

Abstract

Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound <b>11</b> displayed broad potency <i>in vitro</i> against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates. Moreover, <b>11</b> could eliminate both liver and erythrocytic parasites <i>in vivo</i>, kill all morphological erythrocytic parasites with specific potency against schizonts, and show acceptable metabolic stability and pharmacokinetic properties. Western blot analysis, <i>PfHDAC</i> gene knockdown, and enzymatic inhibition experiments collectively confirmed that <i>Pf</i>HDAC1 was the target of <b>11</b>. In summary, <b>11</b> is a structurally novel <i>Pf</i>HDAC1 inhibitor with the potential to prevent and cure malaria, overcome multidrug resistance, and provide a prospective prototype for antimalarial drug research.