Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-]pyridine As a Potential Inhibitor of Cyclin G-Associated Kinase

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Mar 13

PMID 38474466

Authors

Tom Grisez

Nitha Panikkassery Ravi

Mathy Froeyen

Dominique Schols

Luc Van Meervelt

Steven De Jonghe

Wim Dehaen

Affiliations

Soon will be listed here.

Abstract

Disubstituted isothiazolo[4,3-]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-]pyridines remain elusive, a strategy was established to prepare this chemotype, starting from 2,4-dichloro-3-nitropyridine. Selective C-4 arylation using ligand-free Suzuki-Miyaura coupling and palladium-catalyzed aminocarbonylation functioned as key steps in the synthesis. The 3--morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-]pyridine was completely devoid of GAK affinity, in contrast to its 3,5- and 3,6-disubstituted congeners. Molecular modeling was applied to rationalize its inactivity as a GAK ligand.

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