Design and synthesis of novel hydroxamic acid derivatives based on quisinostat as promising antimalarial agents with improved safety

In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through drug repurposing strategy, but its safety matter of concern. Herein, further medicinal chemistry methods were used to identify new chemical entities with greater effectiveness and than quisinostat. total, 38 novel hydroxamic acid derivatives designed synthesized, their in vitro activities systematically investigated. These compounds at nanomolar concentrations showed inhibitory effects on wild-type drug-resistant Plasmodium falciparum strains erythrocyte stage. Among them, compound 30 , after oral administration, resulted complete elimination parasites mice infected yoelii also exhibited better metabolic properties observed work. Mechanistically, upregulated plasmodium histone acetylation, according western blotting, thus suggesting that it exerts inhibition enzymes.