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).
Highlights
Kinases are one of the largest enzyme families of the genome
This paper describes the development of a simple and reliable method that allows the preparation of a library of new thiazolo[5,4-f]quinazolines for which interesting kinase inhibitory activities were observed
The target molecules we studied were thiazolo[5,4-f]quinazolines (C) substituted in position 4 of the pyrimidine ring by an aromatic amine
Summary
More than 500 kinases play an important role in the regulation of most cellular processes. These enzymes are involved in all major diseases, including cancer, neurodegenerative disorders and cardiovascular diseases [1,2,3]. In the course of our work based on microwave-assisted chemistry, we described ten years ago the multistep synthesis of the 8H-thiazolo[5,4-f]quinazolin-9-ones (A) [9,10]. Brief studies of their structure-activity relationships as dual CDK1/GSK-3 kinases inhibitors were described [7]. Kinase inhibition of the compounds was evaluated on Ser/Thr kinases (CDK5, GSK3, DYRK1A, CLK1 and CK1) selected for their strong implications in various human pathologies, especially in AD [3]
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