Discovery of γ-Tetrahydrocarboline Derivatives as Plasmodium falciparum Histone Deacetylase Inhibitors for Treatment of Malaria.

Malaria is a life-threatening infectious disease caused by Plasmodium parasites, and the emergence of widespread resistance to existing therapies underscores the urgent need for novel antimalarial agents. Quisinostat was identified as a Plasmodium falciparum histone deacetylase 1 (PfHDAC1) inhibitor against drug-resistant malaria parasites but suffered from intolerable toxicity. To achieve a potent and safe antimalarial agent, we hypothesized a scaffold hopping and linker optimization strategy, in which a total of 33 new structural γ-tetrahydrocarboline derivatives were synthesized and subjected to comprehensive evaluation. Compound 5ac was identified as a PfHDAC1 inhibitor with favorable safety profiles (Pf3D7 IC50 = 4.1 nM, HepG2 IC50 = 1.5 μM, SI = 358; HEK293T IC50 = 15 μM, SI = 3573), improved physicochemical properties, and potent in vivo antimalarial activity. Mechanistic studies showed that 5ac could downregulate the expression of malaria invasion-related genes. Overall, this study establishes γ-tetrahydrocarboline derivatives as new structurally promising PfHDAC-targeted antimalarial agents.