Synthesis and biological evaluation of new thiazolo [5,4-f]quinazolines as serine/threonine kinases inhibitors

In our continuous effort aiming at preparing novel heterocyclic scaffolds able to modulate the activity of kinases in signal transduction, thiazolo[5,4-f]quinazolines were particularly studied. This presentation describes a novel strategy for a convenient structure-activity-relationship study towards five serine/threonine kinases (CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3α/β) involved in Alzheimer’s disease.

The chemical highlight of this work was the use of Appel salt (4,5-dichloro-1,2,3-dithiazolium chloride) for the conception of 6-amino-2-cyanobenzo[d]thiazole-7-carboxylate derivatives as a versatile molecular platform from the 5-nitroanthranilic acid. Thus, introduction of various aliphatic, aromatic or amino substituents at position 8 was best achieved by one-pot DMFDMA-mediated cyclisation. Transformation of carbonitrile group into various chemical functions (e.g. imidate, ester, amidine...) allowed the efficient preparation of a library of novel thiazoloquinazoline derivatives. The first biological results have identified great and selective inhibition against DYRK1A and DYRK1B. The more active compounds are imidate derivatives exhibiting inhibitory activity in a subnanomolar range against DYRK1A.