2. Academic Validation
  3. Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety

Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety

  • J Med Chem. 2022 Mar 10;65(5):4156-4181. doi: 10.1021/acs.jmedchem.1c01993.
Manjiong Wang 1,  Tongke Tang 2 3,  Ruoxi Li 1,  Zhenghui Huang 2,  Dazheng Ling 1,  Lulu Zheng 1,  Yan Ding 4,  Taiping Liu 4,  Wenyue Xu 4,  Feng Zhu 5,  Hui Min 5,  Rachasak Boonhok 5,  Fei Mao 1,  Jin Zhu 1,  Xiaokang Li 1,  Lubin Jiang 2 3,  Jian Li 1 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, P.R. China.
  • 4 Department of Pathogenic Biology, Army Medical University, Chongqing 400038, China.
  • 5 Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • 6 College of Pharmacy and Chemistry, Dali University, 5 Xue Ren Road, Dali 671000, China.
  • 7 Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
PMID: 35175762 DOI: 10.1021/acs.jmedchem.1c01993
Abstract

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant Parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Additionally, mechanistic studies via molecular docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1 Enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was PfHDAC1. In summary, we discovered the promising candidate PfHDAC1 Inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

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