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Synthesis and biological evaluation of new thiazolo [5,4-f]quinazolines as serine/threonine kinases inhibitors
* 1 , 1 , 2 , 2 , 2 , 3
1  Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, F-76000 Rouen, France
2  Diaxonhit, 65 boulevard Masséna, Paris F-75013, France
3  Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France.

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

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.

Keywords: thiazolo[5,4-f]quinazolines; serine/threonine kinases ; Appel salt; DMFDMA-mediated cyclisation