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

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 11 displayed broad
potency in vitro against several multiresistant malarial
parasites, especially two artemisinin-resistant clinical isolates.
Moreover, 11 could eliminate both liver and erythrocytic
parasites in vivo, kill all morphological erythrocytic
parasites with specific potency against schizonts, and show acceptable
metabolic stability and pharmacokinetic properties. Western blot analysis, PfHDAC gene knockdown, and enzymatic inhibition experiments
collectively confirmed that PfHDAC1 was the target
of 11. In summary, 11 is a structurally
novel PfHDAC1 inhibitor with the potential to prevent
and cure malaria, overcome multidrug resistance, and provide a prospective
prototype for antimalarial drug research.