Development of Kinase Inhibitors via Metal-Catalyzed C–H Arylation of 8-Alkyl-thiazolo[5,4-f]-quinazolin-9-ones Designed by Fragment-Growing Studies

Florence Couly (1) , Marine Harari (1) , Carole Dubouilh-Benard (1) , Laëtitia Bailly (1) , Emilie Petit (1) , Julien Diharce (2) , Pascal Bonnet (3) , Laurent Meijer (4) , Corinne Fruit (1) , Thierry Besson (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 ICN - Institut de Chimie de Nice
3 ICOA - Institut de Chimie Organique et Analytique
4 ManRos Therapeutics

Efficient metal catalyzed C–H arylation of 8-alkyl-thiazolo[5,4-f]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, FC162 (4c) exhibits nanomolar IC50 values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor

Keywords: DYRK1A; CDK5; protein kinases; CLK1; GSK-3; CK1; C-H arylation; thiazolo[5; 4-f ]quinazolin-9(8H)-ones; microwave-assisted synthesis

Domains: Medicinal Chemistry; Organic chemistry

Florence Couly, Marine Harari, Carole Dubouilh-Benard, Laëtitia Bailly, Emilie Petit, et al.. Development of Kinase Inhibitors via Metal-Catalyzed C–H Arylation of 8-Alkyl-thiazolo[5,4-f]-quinazolin-9-ones Designed by Fragment-Growing Studies. Molecules, 2018, 23 (9), pp.2181. ⟨10.3390/molecules23092181⟩. ⟨hal-02024491⟩