Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-b]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase-Reference-Cited by-同舟云学术

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

Published:2024-02-22 Issue:5 Volume:29 Page:954
ISSN:1420-3049
Container-title:Molecules
language:en
Short-container-title:Molecules

Author:

Grisez Tom¹^ORCID,Ravi Nitha Panikkassery¹^ORCID,Froeyen Mathy²^ORCID,Schols Dominique³^ORCID,Van Meervelt Luc⁴^ORCID,De Jonghe Steven³^ORCID,Dehaen Wim¹^ORCID

Affiliation:

1. Department of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium

2. Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, P.O. Box 1041, B-3000 Leuven, Belgium

3. Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium

4. Department of Chemistry, Biomolecular Architecture, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium

Abstract

Disubstituted isothiazolo[4,3-b]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-b]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-N-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]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.

Funder

Department of Defense (DoD, United States Army Medical Research Acquisition Activity, USAMRAA

Research Foundation—Flanders

Hercules Foundation of the Flemish Government

Publisher

MDPI AG

Link

https://www.mdpi.com/1420-3049/29/5/954/pdf

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