Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat

Abstract

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.

Nano-Assembly of Quisinostat and Biodegradable Macromolecular Carrier Results in Supramolecular Complexes with Slow-Release Capabilities

“…Quisinostat demonstrates high antitumoral efficacy when dissolved in DMSO-water mixture with selectivity index of 9 [48]. In vitro anti-proliferative activity of quisinostat-PPEG complexes in the absence of co-solvent was demonstrated using two cell lines-A549 lung cancer cells and WM115 human melanoma cells.…”

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

“…Ruoxi Li et al reported this year [ 45 ] their results of a new series of Pf HDAC1 inhibitors with dual-stage antimalarial potency and improved safety which was based on structural modifications of quisinostat. Quisinostat (16) showed potent antimalarial in vitro activity [ 46 ] and inhibited both wild-type and drug-resistant P. falciparum strains with IC 50 values 5–7 nM.…”

“…The authors also point out that several compounds (31c, 31e, 31s, 31t) developed in the series showed interesting antiplasmodial activities, IC 50 (Pf 3D7) = 0.0052-0.12 µM, and good selectivity indexes, SI = 417-889, thus, representing a valuable starting point for the development of novel drug candidates (Table 3). [45] their results of a new series of Pf HDAC1 inhibitors with dual-stage antimalarial potency and improved safety which was based on structural modifications of quisinostat. Quisinostat (16) showed potent antimalarial in vitro activity [46] and inhibited both wild-type and drug-resistant P. falciparum strains with IC 50 values 5-7 nM.…”

Repurposing Anticancer Drugs To Tackle Malaria

“…Since PfHDAC1 remains a very attractive drug target, further chemical optimization of JX21108 should be undertaken. Most recently, while main problem of the series remains the potential toxicity, the same research group reported the synthesis of a novel quisinostat derivative combining enhanced pharmacokinetics, multistage killing activity, and high potency against P. falciparum multiresistant strains [12] . Taken together, these data suggest that targeting the epigenome machinery may constitute a relevant alternative strategy to cure and prevent malaria, overcome antimalarial resistance, and control human‐to‐mosquito transmission, opening a new avenue for reaching the ambitious but indispensable goal of malaria eradication.…”

“…ChemMedChem the same research group reported the synthesis of a novel quisinostat derivative combining enhanced pharmacokinetics, multistage killing activity, and high potency against P. falciparum multiresistant strains. [12] Taken together, these data suggest that targeting the epigenome machinery may constitute a relevant alternative strategy to cure and prevent malaria, overcome antimalarial resistance, and control human-to-mosquito transmission, opening a new avenue for reaching the ambitious but indispensable goal of malaria eradication. Experiments showed that JX21108 could eliminate various stages of the parasites in vivo.…”