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.

疟疾是由疟原虫引发的致命传染病，现有抗疟治疗手段的广泛耐药性凸显了开发新型抗疟药物的迫切需求。奎司他特（Quisinostat）被鉴定为可靶向耐药疟原虫的恶性疟原虫组蛋白去乙酰化酶1（Plasmodium falciparum histone deacetylase 1, PfHDAC1）抑制剂，但存在难以耐受的毒副作用。为获得强效且安全的抗疟药物，本研究提出骨架跃迁与连接子优化策略，共合成33种全新结构的γ-四氢咔啉衍生物并开展综合评价。其中化合物5ac被鉴定为PfHDAC1抑制剂，具备良好的安全性谱（Pf3D7半数抑制浓度（half maximal inhibitory concentration, IC50）=4.1 nM，HepG2细胞IC50=1.5 μM，治疗指数（selectivity index, SI）=358；HEK293T细胞IC50=15 μM，SI=3573），理化性质得到改善，且体内抗疟活性强劲。机制研究表明，化合物5ac可下调疟原虫入侵相关基因的表达。综上，本研究确立了γ-四氢咔啉衍生物作为一类极具开发前景的靶向PfHDAC的新型抗疟候选药物。