Synthesis of 3-heteroaryl-pyrrolo[2,3-b]pyridines as potent inhibitors of AP-2-associated protein kinase 1 (AAK1) with antiviral activity

  • Eur J Med Chem. 2024 Dec 15:280:116967. doi: 10.1016/j.ejmech.2024.116967.
Nitha Panikkassery Ravi  1 ,  Wout Van Eynde  2 ,  Marwah Karim  3 ,  Do Hoang Nhu Tran  3 ,  Aditi Agrawal  3 ,  Dominique Schols  4 ,  Arnout Voet  2 ,  Shirit Einav  5 ,  Wim Dehaen  1 ,  Steven De Jonghe  6
Affiliations
  • 1. KU Leuven, Sustainable Chemistry for Metals and Molecules, Department of Chemistry, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
  • 2. KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Laboratory of Biomolecular Modelling and Design, Celestijnenlaan 200G, box 2403, B-3001 Leuven, Belgium.
  • 3. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular Structural and Translational Virology Research Group, Herestraat 49, box 1043, B-3000 Leuven, Belgium.
  • 5. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • 6. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular Structural and Translational Virology Research Group, Herestraat 49, box 1043, B-3000 Leuven, Belgium. Electronic address: [email protected].
PMID: 39427517 DOI: 10.1016/j.ejmech.2024.116967
Abstract

Inhibition of AP-2-associated protein kinase 1 (AAK1) has been shown to be a promising avenue for the development of broad-spectrum Antiviral agents. On a previously described AAK1 Inhibitor based on a pyrrolo[2,3-b]pyridine scaffold, the concept of isosterism was applied, by replacing a carboxamide linker by various five-membered heterocycles. It led to the discovery of a novel series of AAK1 inhibitors with IC50 values in the low nM range, that also displayed Antiviral activity against the Dengue Virus and Venezuelan equine encephalitis virus.

Keywords
7-Azaindole; Adaptor-associated kinase 1; Antivirals; pyrrolo[2-3-b]pyridine.
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