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 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.
Highlights
Protein kinases catalyze protein phosphorylation, a key cellular regulatory mechanism, which is frequently dysregulated in human diseases
This paper describes the convenient preparation of a new methyl 9-(arylamino)thiazolo[5,4f]quinazoline-2-carbimidate derivative library for which highly potent DYRK1A/1B kinase inhibitory activities are observed
The target molecules we studied were thiazolo[5,4-f]quinazolines substituted in position 4 of the pyrimidine ring by an aromatic amine
Summary
Protein kinases catalyze protein phosphorylation, a key cellular regulatory mechanism, which is frequently dysregulated in human diseases These enzymes are involved in all major diseases, including cancer, neurodegenerative disorders and cardiovascular diseases [1,2,3]. In the course of our work, the multistep synthesis of a novel 9-(aryl)-N-(2-alkyl)thiazolo[5,4f]quinazoline library (A in Scheme 1) was recently described [9] These compounds were designed as 6,6,5-tricyclic homologs of the basic 4-aminoquinazoline pharmacophore, which is present in approximately 80% of ATP-competitive kinase inhibitors that have received approval for the treatment of cancer [10]. Brief studies of their structure-activity relationships as kinase inhibitors were realized
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