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

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

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: steven.dejonghe@kuleuven.be.
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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