Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I
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-ami...
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doaj-6ca67dd9f9384e47b187d657d60da8d12020-11-24T21:35:41ZengMDPI AGMolecules1420-30492014-09-011910155461557110.3390/molecules191015546molecules191015546Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part IAlicia Foucourt0Damien Hédou1Carole Dubouilh-Benard2Laurent Désiré3Anne-Sophie Casagrande4Bertrand Leblond5Nadège Loäec6Laurent Meijer7Thierry Besson8Normandie 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, FranceNormandie 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, FranceNormandie 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, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceProtein Phosphorylation & Human Disease group, CNRS, Station Biologique, Roscoff F-29680, FranceManRos Therapeutics, Centre de Perharidy, Roscoff F-29680, FranceNormandie 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, FranceThe 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).http://www.mdpi.com/1420-3049/19/10/15546thiazolo[5,4-f]quinazolineskinases inhibitorsDYRK1AGSK3α/βmicrowave-assisted chemistryDimroth rearrangementappel salt |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Laurent Désiré Anne-Sophie Casagrande Bertrand Leblond Nadège Loäec Laurent Meijer Thierry Besson |
spellingShingle |
Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Laurent Désiré Anne-Sophie Casagrande Bertrand Leblond Nadège Loäec Laurent Meijer Thierry Besson Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I Molecules thiazolo[5,4-f]quinazolines kinases inhibitors DYRK1A GSK3α/β microwave-assisted chemistry Dimroth rearrangement appel salt |
author_facet |
Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Laurent Désiré Anne-Sophie Casagrande Bertrand Leblond Nadège Loäec Laurent Meijer Thierry Besson |
author_sort |
Alicia Foucourt |
title |
Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I |
title_short |
Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I |
title_full |
Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I |
title_fullStr |
Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I |
title_full_unstemmed |
Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I |
title_sort |
design and synthesis of thiazolo[5,4-f]quinazolines as dyrk1a inhibitors, part i |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2014-09-01 |
description |
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). |
topic |
thiazolo[5,4-f]quinazolines kinases inhibitors DYRK1A GSK3α/β microwave-assisted chemistry Dimroth rearrangement appel salt |
url |
http://www.mdpi.com/1420-3049/19/10/15546 |
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