Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

Amélie Bruel (1) , Romain Bénéteau (1) , Mylène Chabanne (1) , Olivier Lozach (2) , Rémy Le Guevel (3) , Myriam Ravache (3) , Hélène Bénédetti (4) , Laurent Meijer (5, 2) , Cédric Logé (1) , Jean-Michel Robert (1)

1 IICiMed - Cibles et Médicaments des Infections et de l'Immunité
2 P3H - Phophorylation de protéines et Pathologies Humaines
3 GFAS - Génétique fonctionnelle, agronomie et santé [IFR 140]
4 CBM - Centre de biophysique moléculaire
5 ManRos Therapeutics

New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.

Keywords: 4-Oxo-3; 4-dihydro-5H-pyridazino[4; 5-b]indole; Pyridazin-3(2H)-one; DYRK1A inhibitors; Anti-proliferative effects; Synthesis

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Biochemistry [q-bio.BM]

Amélie Bruel, Romain Bénéteau, Mylène Chabanne, Olivier Lozach, Rémy Le Guevel, et al.. Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors. Bioorganic and Medicinal Chemistry Letters, 2014, 24 (21), pp.5037 - 5040. ⟨10.1016/j.bmcl.2014.09.017⟩. ⟨hal-01086026⟩