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

Molecules

Alicia Foucourt²  Damien Hຝou²  Carole Dubouilh-Benard²  Laurent Désiré⁴  Anne-Sophie Casagrande⁴  Bertrand Leblond⁴  Nadège Lo³  Laurent Meijer¹  Thierry Besson² 

[1] ManRos Therapeutics, Centre de Perharidy, Roscoff F-29680, France; E-Mail:;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:;Protein Phosphorylation & Human Disease group, CNRS, Station Biologique, Roscoff F-29680, France; E-Mail:;Diaxonhit, 65 boulevard Masséna, Paris F-75013, France; E-Mails:

关键词: thiazolo[5;    4-f]quinazolines;    kinases inhibitors;    DYRK1A;    GSK3α/β;    microwave-assisted chemistry;    Dimroth rearrangement;    appel salt;   

DOI  :  10.3390/molecules191015546

来源: mdpi

【 摘 要 】

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).

【 授权许可】

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