title: Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II.
abstract: The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases.
authors.affiliation: Normandie Univ, Laboratoire C.O.B.R.A., UMR 6014 and FR 3038; Univ 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 Univ, Laboratoire C.O.B.R.A., UMR 6014 and FR 3038; Univ 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 Univ, Laboratoire C.O.B.R.A., UMR 6014 and FR 3038; Univ 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. angelique.girard@diaxonhit.com.
authors.forename: Angélique
authors.initials: A
authors.lastname: Girard
authors.affiliation: Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. taverne.thierry@gmail.com.
authors.forename: Thierry
authors.initials: T
authors.lastname: Taverne
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. laurent.desire@diaxonhit.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.affiliation: Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. bertrandleblond@hotmail.com.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.affiliation: Normandie Univ, Laboratoire C.O.B.R.A., UMR 6014 and FR 3038; Univ 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; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000097603:Dyrk Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D000097603:Dyrk Kinases