title: Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part I.
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).
authors.affiliation: 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. foucourtalicia@aol.com.
authors.forename: Alicia
authors.initials: A
authors.lastname: Foucourt
authors.affiliation: 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. damien.hedou@etu.univ-rouen.fr.
authors.forename: Damien
authors.initials: D
authors.lastname: Hédou
authors.affiliation: 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. carole.dubouilh@univ-rouen.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Dubouilh-Benard
authors.affiliation: Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. laurent.desire@diaxonhit.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.affiliation: Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. anne-sophie.casagrande@diaxonhit.com.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Casagrande
authors.affiliation: Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. bertrandleblond@hotmail.com.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.affiliation: Protein Phosphorylation & Human Disease group, CNRS, Station Biologique, Roscoff F-29680, France. meijer@manros-therapeutics.com.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loäec
authors.affiliation: ManRos Therapeutics, Centre de Perharidy, Roscoff F-29680, France. meijer@manros-therapeutics.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: 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. thierry.besson@univ-rouen.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Besson
mesh_terms: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles; D000097603:Dyrk Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D013844:Thiazoles; D000097603:Dyrk Kinases