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.