Structure-activity relationship study of the pyridine moiety of isothiazolo[4,3-b]pyridines as antiviral agents targeting cyclin G-associated kinase

Belén Martinez-Gualda; Szu-Yuan Pu; Mathy Froeyen; Piet Herdewijn; Shirit Einav; Steven De Jonghe

doi:10.1016/j.bmc.2019.115188

Structure-activity relationship study of the pyridine moiety of isothiazolo[4,3-b]pyridines as antiviral agents targeting cyclin G-associated kinase

Bioorg Med Chem. 2020 Jan 1;28(1):115188. doi: 10.1016/j.bmc.2019.115188. Epub 2019 Nov 11.

Authors

Belén Martinez-Gualda¹, Szu-Yuan Pu², Mathy Froeyen¹, Piet Herdewijn¹, Shirit Einav², Steven De Jonghe³

Affiliations

¹ KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
² 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.
³ KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].

PMID: 31757682
DOI: 10.1016/j.bmc.2019.115188

Abstract

Previously, we reported the discovery of 3,6-disubstituted isothiazolo[4,3-b]pyridines as potent and selective cyclin G-associated kinase (GAK) inhibitors with promising antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK binding affinity and antiviral activity against dengue virus.

Keywords: Antiviral drugs; Cyclin G-associated kinase; Dengue virus; Isothiazolo[4,3-b]pyridine; Kinase inhibitor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line
Dengue Virus / drug effects*
Dose-Response Relationship, Drug
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
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*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antiviral Agents
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyridines
Thiazoles
isothiazolo(5,4-b)pyridine
GAK protein, human
Protein Serine-Threonine Kinases
pyridine