Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.
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.
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