2. Academic Validation
  3. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II

Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II

  • Molecules. 2014 Sep 26;19(10):15411-39. doi: 10.3390/molecules191015411.
Alicia Foucourt 1,  Damien Hédou 2,  Carole Dubouilh-Benard 3,  Angélique Girard 4,  Thierry Taverne 5,  Anne-Sophie Casagrande 6,  Laurent Désiré 7,  Bertrand Leblond 8,  Thierry Besson 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. angelique.girard@diaxonhit.com.
  • 5 Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. taverne.thierry@gmail.com.
  • 6 Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. anne-sophie.casagrande@diaxonhit.com.
  • 7 Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. laurent.desire@diaxonhit.com.
  • 8 Diaxonhit, 65 boulevard Masséna, Paris F-75013, France. bertrandleblond@hotmail.com.
  • 9 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.
PMID: 25264830 DOI: 10.3390/molecules191015411
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.

Figures
Products