Discovery of γ-Tetrahydrocarboline Derivatives as <i>Plasmodium falciparum</i> Histone Deacetylase Inhibitors for Treatment of Malaria

Malaria is a life-threatening infectious disease caused by <i>Plasmodium</i> parasites, and the emergence of widespread resistance to existing therapies underscores the urgent need for novel antimalarial agents. Quisinostat was identified as a <i>Plasmodium falciparum</i> histone deacetylase 1 (<i>Pf</i>HDAC1) 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 <b>5ac</b> was identified as a <i>Pf</i>HDAC1 inhibitor with favorable safety profiles (<i>Pf</i>3D7 IC₅₀ = 4.1 nM, HepG2 IC₅₀ = 1.5 μM, SI = 358; HEK293T IC₅₀ = 15 μM, SI = 3573), improved physicochemical properties, and potent <i>in vivo</i> antimalarial activity. Mechanistic studies showed that <b>5ac</b> could downregulate the expression of malaria invasion-related genes. Overall, this study establishes γ-tetrahydrocarboline derivatives as new structurally promising <i>Pf</i>HDAC-targeted antimalarial agents.