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

Nitha Panikkassery Ravi; Wout Van Eynde; Marwah Karim; Do Hoang Nhu Tran; Aditi Agrawal; Dominique Schols; Arnout Voet; Shirit Einav; Wim Dehaen; Steven De Jonghe

doi:10.1016/j.ejmech.2024.116967

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. Epub 2024 Oct 14.

Authors

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.

MeSH terms

Animals
Antiviral Agents* / chemical synthesis
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Dengue Virus / drug effects
Dengue Virus / enzymology
Dose-Response Relationship, Drug
Humans
Microbial Sensitivity Tests
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Pyridines* / chemical synthesis
Pyridines* / chemistry
Pyridines* / pharmacology
Pyrroles* / chemical synthesis
Pyrroles* / chemistry
Pyrroles* / pharmacology
Structure-Activity Relationship

Substances

Antiviral Agents
Pyridines
Protein Kinase Inhibitors
Pyrroles
AAK1 protein, human
Protein Serine-Threonine Kinases
pyrrolo(2, 3-b)pyridine