Discovery of antivirally active inhibitors of adaptor protein-2 associated kinase 1 based on various bicyclic heteroaromatic scaffolds derived from a 7-azaindole analogue

  • Eur J Med Chem. 2025 Jul 24:299:118001. doi: 10.1016/j.ejmech.2025.118001.
Stijn Anthonissen  1 ,  Wout Van Eynde  2 ,  Marwah Karim  3 ,  Ling-Jie Gao  4 ,  Do Hoang Nhu Tran  3 ,  Dominique Schols  5 ,  Arnout Voet  2 ,  Shirit Einav  6 ,  Wim Dehaen  1 ,  Steven De Jonghe  7
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 Pharmaceutical and Pharmacological Sciences, Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, B-3000, Leuven, Belgium.
  • 5. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, B-3000, Leuven, Belgium.
  • 6. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • 7. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, B-3000, Leuven, Belgium. Electronic address: [email protected].
PMID: 40803164 DOI: 10.1016/j.ejmech.2025.118001
Abstract

Adaptor protein-2 associated kinase 1 (AAK1) has been proposed as a promising host target for the development of broad-spectrum Antiviral agents. Different regioisomers, as well as scaffolds that were not explored before for their AAK1 affinity, were prepared that were derived from a known and potent 7-azaindole-based AAK1 Inhibitor. This effort led to the discovery of various pyrrolo[2,3-b]pyridines, pyrazolo[3,4-b]pyridines and pyrazolo[3,4-d]pyrimidines with low nanomolar AAK1 binding affinity. The AAK1 data were rationalized by molecular modeling. Selected congeners displayed Antiviral activity against Dengue Virus and Venezuelan equine encephalitis virus.

Keywords
Adaptor protein-2 associated kinase 1; Antivirals; Azaindole; Pyrrolo[2,3-b]pyridine.
Products