Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors

Mohamed Elagawany; Mohamed A Ibrahim; Hany Emary Ali Ahmed; A Sh El-Etrawy; Adel Ghiaty; Zakaria K Abdel-Samii; Said A El-Feky; Jürgen Bajorath

doi:10.1016/j.bmcl.2013.02.027

Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2007-13. doi: 10.1016/j.bmcl.2013.02.027. Epub 2013 Feb 13.

Authors

Mohamed Elagawany¹, Mohamed A Ibrahim, Hany Emary Ali Ahmed, A Sh El-Etrawy, Adel Ghiaty, Zakaria K Abdel-Samii, Said A El-Feky, Jürgen Bajorath

Affiliation

¹ Laboratoire d'innovation thérapeutique, UMR 7200, Faculté de Pharmacie, Université de Strasbourg, 74-route du Rhin, BP 60024, 67401 ILLKIRCH Cedex, France. alfath_tours@yahoo.com

PMID: 23453843
DOI: 10.1016/j.bmcl.2013.02.027

Abstract

The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Casein Kinase I / antagonists & inhibitors
Casein Kinase I / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 5 / antagonists & inhibitors
Cyclin-Dependent Kinase 5 / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Dyrk Kinases
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism
HCT116 Cells
HL-60 Cells
Humans
Models, Molecular
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Phthalazines
Protein Kinase Inhibitors
Pyridazines
Protein-Tyrosine Kinases
Casein Kinase I
Cyclin-Dependent Kinase 5
Protein Serine-Threonine Kinases
Glycogen Synthase Kinase 3