Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety

Our previous work found that the
clinical histone deacetylase (HDAC)
inhibitor quisinostat exhibited a significant antimalarial effect
but with severe toxicity. In this work, 35 novel derivatives were
designed and synthesized based on quisinostat as the lead compound,
and their in vitro antimalarial activities and cytotoxicities were
systematically evaluated. Among them, JX35 showed potent
inhibition against both wild-type and multidrug-resistant parasite
strains and displayed a significant in vivo killing effect against
all life cycles of parasites, including the blood stage, liver stage,
and gametocyte stage, indicating its potential for the simultaneous
treatment, chemoprevention, and blockage of malaria transmission.
Compared with quisinostat, JX35 exhibited stronger antimalarial
efficacy, more adequate safety, and good pharmacokinetic properties.
Additionally, mechanistic studies via molecular docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1
enzyme inhibition assays jointly indicated that the antimalarial target
of JX35 was PfHDAC1. In summary, we
discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects
and lower toxicity than quisinostat.