Synthesis and biological evaluation of linear thiazolo[4,5-g] and [5,4-g]quinazolines, analogues of V-shaped DYRK1A inhibitors EHT1610 and FC162.

The synthesis of new heterocyclic structures is a crucial issue in medicinal chemistry, which is constantly seeking for new active molecules. In the past 20 years, our research group has focused on the synthesis of DYRK1A inhibitors containing a thiazole ring fusionned with a quinazolin-4-one, a heterocyclic system present in many natural or synthetic molecules of biological interest. Two highly affine compounds, EHT1610 and FC162 were then identified and particularly studied. Docking studies highlighted the role of the V-shape of our compounds in their ability to inhibit DYRK1A. Recently, we described a synthetic method for access to 2-cyanobenzothiazoles from N-Arylcyanothioformamides via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S bond formation. This regiospecific cyclization incited us to develop novel synthetic routes to obtain regioisomers of EHT1610 and FC162, our reference compounds. After an optimization step, this methodology allowed the synthesis of linear thiazolo[4,5-g] and [5,4-g] quinazoline regioisomers and chemical analogs of the two V-shaped leads. Preliminary results of kinase inhibition and cytotoxic evaluation of the target compounds are presented in this communication.