Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II

Alicia Foucourt (1) , Damien Hédou (1) , Carole Dubouilh-Benard (1) , Angelique Girard (2) , Thierry Taverne (2) , Anne-Sophie Casagrande (2) , Laurent Désiré (2) , Bertrand Leblond (2) , Thierry Besson (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 Diaxonhit

The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases.

Mots clés: EHT 3356; EHT 9851; EHT 1610; EHT 6840; EHT 5372; Dimroth rearrangement; Microwave-assisted chemistry; DYRK1B; DYRK1A; Kinase inhibitors; Thiazolo[5-4-f]quinazolines

Domaines: Chimie organique; Chimie analytique; Catalyse; Chimie thérapeutique; Chimie théorique et/ou physique

Alicia Foucourt, Damien Hédou, Carole Dubouilh-Benard, Angelique Girard, Thierry Taverne, et al.. Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II. Molecules, 2014, 19 (10), pp.15411-15439. ⟨10.3390/molecules191015411⟩. ⟨hal-01135223⟩