2. Academic Validation
  3. Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

  • Eur J Med Chem. 2020 Feb 15;188:112012. doi: 10.1016/j.ejmech.2019.112012.
Xiaofei Liang 1,  Zongru Jiang 2,  Zhenghui Huang 3,  Feng Li 2,  Cheng Chen 2,  Chen Hu 1,  Wenliang Wang 2,  Zhenquan Hu 1,  Qingwang Liu 4,  Beilei Wang 1,  Li Wang 2,  Ziping Qi 1,  Jing Liu 5,  Lubin Jiang 6,  Qingsong Liu 7
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 2 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
  • 3 Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China.
  • 5 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China. Electronic address: jingliu@hmfl.ac.cn.
  • 6 Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China. Electronic address: lbjiang@ips.ac.cn.
  • 7 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address: qsliu97@hmfl.ac.cn.
PMID: 31911293 DOI: 10.1016/j.ejmech.2019.112012
Abstract

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.

Keywords

Blood stage; Kinase inhibitor; Liver stage; Malaria; PI4K kinase.

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