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

  • J Med Chem. 2026 Jan 22;69(2):1434-1453. doi: 10.1021/acs.jmedchem.5c02869.
Hao Ni  1 ,  Yunan Qian  2 ,  Zeguang Dai  3 ,  Yuan Cai  2  4 ,  Long Cao  2 ,  Jiaming Li  1 ,  Zhencheng Lai  1 ,  Xueping Hu  5 ,  Zhenghui Huang  2 ,  Lubin Jiang  2 ,  Sunliang Cui  1  3
Affiliations
  • 1. Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3. School of Pharmaceutical Science, Hangzhou Medical College, Hangzhou 310053, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao 266237, China.
PMID: 41485139 DOI: 10.1021/acs.jmedchem.5c02869
Abstract

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.

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