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 Pf HDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was Pf HDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

Automated summary

This study designed and synthesized 35 novel derivatives based on quisinostat, with JX35 showing significant antimalarial effects in both in vitro and in vivo studies. JX35 exhibited potent inhibition against various parasite strains, suggesting its potential for simultaneous treatment, chemoprevention, and blocking malaria transmission. Mechanistic studies indicated that JX35 targets Pf HDAC1, showing stronger triple-stage antimalarial effects and lower toxicity compared to quisinostat.