Design and synthesis of novel hydroxamic acid derivatives based on quisinostat as promising antimalarial agents with improved safety

Preprint | 
10.55415/deep-2022-0024.v1
This is not the most recent version. There is anewer versionof this content available.
Manjiong Wang#
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Tongke Tang#
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China,School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, P.R. China
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China,School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, P.R. China
Zhenghui Huang
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Ruoxi Li
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Dazheng Ling
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Jin Zhu
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Lubin Jiang*
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China,School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, P.R. China
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China,School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, P.R. China
Jian Li*
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China,Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, Hainan, China,Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China,Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali 671000, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China,Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, Hainan, China,Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China,Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali 671000, China
Xiaokang Li*
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

# contributed equally to this work, * Corresponding author

Abstract

In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through drug repurposing strategy, but its safety was of concern. Herein, further medicinal chemistry method was used to find new chemical entities with greater effectiveness and security than quisinostat. Totally, 38 novel hydroxamic acid derivatives were designed and synthesized and their in vitro antimalarial activities were systematically investigated. These compounds showed inhibitory effect on wild and drug-resistant Plasmodium falciparum strains in erythrocyte stage at nanomole concentrations. Among them, compound 30 displayed completely elimination of parasites in Plasmodium yoelii infected mice through oral administration, and also exhibited better safety and metabolic properties compared with our previous work. Moreover, compound 30 was proved that can upregulate the acetylation level of plasmodium histone by western blot, suggesting it exerted antimalarial effect by the inhibition of PfHDAC enzymes.
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Supplementary Material
  1. AMM_Supporting_Information.pdf
Keywords
Antimalarial ;  Drug repurposing ;  Hydroxamic acid ;  Erythrocyte stage ;  Drug resistance
Subject Area
Gastroenterology
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  • 18 Mar 2022 18:40 Version 1
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