Design, synthesis and therapeutic evaluation of novel antimalarial derivatives based on the clinical antitumor candidate drug Quisinostat

[Display omitted] •Compound 33 and 37 showed significant antimalarial activity against wild-type and multidrug-resistant malarial parasites.•Compound 33 and 37 completely eliminated parasites with better safety than Quisinostat in P. yoelii infected mice model.•Compared to Quisinostat, compounds 33 and 37 reduced cytotoxicity and improved metabolic properties. In previous studies, we identified the clinical antitumor drug candidate Quisinostat is a potent Plasmodium falciparum histone deacetylase (PfHDAC) inhibitor with significant activity against drug-resistant malaria but with severe toxicity. To delve deeper into its antimalarial potential, herein we designed and synthesized 36 novel analogues of Quisinostat and systematically evaluated their antimalarial activities and cytotoxicity. Among them, compounds 33 and 37 could effectively eliminate both wild-type and multidrug resistant P. falciparum parasites along with significantly attenuated cytotoxicity, and their metabolic properties were also notably improved. Western blot analysis showed that 33 and 37 upregulated Plasmodium histone acetylation, suggesting that they exerted antimalarial effects through inhibition of PfHDAC like Quisinostat. Furthermore, compounds 33 and 37 also displayed significant antimalarial therapeutic effect and improved animal safety in rodent malaria model. Collectively, 33 and 37 were structurally novel PfHDAC inhibitors and promising antimalarial lead compounds for the next generation of antimalarial drug research.