Synthesis of bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation

Damien Hédou (1) , Carole Dubouilh-Benard (1) , N. Loaëc (2) , L. Meijer , Corinne Fruit (1) , Thierry Besson (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 P3H - Phophorylation de protéines et Pathologies Humaines

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.

Mots clés: CLK1; CK1; Hügershoff reaction; Thiazolo[5 4-f]quinazolin-9(8H)-ones; DYRK1A; GSK-3; CDK5; Protein kinases; Microwave-assisted synthesis

Domaines: Chimie organique; Chimie thérapeutique; Catalyse

Damien Hédou, Carole Dubouilh-Benard, N. Loaëc, L. Meijer, Corinne Fruit, et al.. Synthesis of bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation. Molecules, 2016, 21 (6), pp.794. ⟨10.3390/molecules21060794⟩. ⟨hal-02046212⟩