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Molecules 2014, 19(10), 15546-15571; doi:10.3390/molecules191015546

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

1
Normandie Université, Laboratoire C.O.B.R.A., UMR 6014 and FR 3038; Université de Rouen; INSA de Rouen; CNRS, Bâtiment I.R.C.O.F. rue Tesnière, Mont-Saint-Aignan F-76821, France
2
Diaxonhit, 65 boulevard Masséna, Paris F-75013, France
3
Protein Phosphorylation & Human Disease group, CNRS, Station Biologique, Roscoff F-29680, France
4
ManRos Therapeutics, Centre de Perharidy, Roscoff F-29680, France
*
Author to whom correspondence should be addressed.
Received: 29 July 2014 / Revised: 19 September 2014 / Accepted: 22 September 2014 / Published: 29 September 2014
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Abstract

The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) a versatile molecular platform for the synthesis of various bioactive derivatives. Kinase inhibition of the final compounds was evaluated on a panel of four Ser/Thr kinases (DYRK1A, CDK5, CK1 and GSK3) chosen for their strong implications in various regulation processes, especially Alzheimer’s disease (AD). In view of the results of this preliminary screening, thiazolo[5,4-f]quinazoline scaffolds constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. Among the compounds of this novel chemolibrary, 7i, 8i and 9i inhibited DYRK1A with IC50 values ranging in the double-digit nanomolar range (40, 47 and 50 nM, respectively). View Full-Text
Keywords: thiazolo[5,4-f]quinazolines; kinases inhibitors; DYRK1A; GSK3α/β; microwave-assisted chemistry; Dimroth rearrangement; appel salt thiazolo[5,4-f]quinazolines; kinases inhibitors; DYRK1A; GSK3α/β; microwave-assisted chemistry; Dimroth rearrangement; appel salt
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Foucourt, A.; Hédou, D.; Dubouilh-Benard, C.; Désiré, L.; Casagrande, A.-S.; Leblond, B.; Loäec, N.; Meijer, L.; Besson, T. Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I. Molecules 2014, 19, 15546-15571.

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