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

Molecules

Alicia Foucourt¹  Damien Hຝou¹  Carole Dubouilh-Benard¹  Angélique Girard²  Thierry Taverne²  Anne-Sophie Casagrande²  Laurent Désiré²  Bertrand Leblond²  Thierry Besson¹ 

[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; E-Mails:;Diaxonhit, 65 boulevard Masséna, Paris F-75013, France; E-Mails:

关键词: thiazolo[5;    4-f]quinazolines;    kinase inhibitors;    DYRK1A;    DYRK1B;    microwave-assisted chemistry;    Dimroth rearrangement;    EHT 5372;    EHT 6840;    EHT 1610;    EHT 9851;    EHT 3356;   

DOI  :  10.3390/molecules191015411

来源: mdpi

【 摘 要 】

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 Alzeimer 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.

【 授权许可】

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© 2014 by the authors; licensee MDPI, Basel, Switzerland.