Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Sep 26;19(10):15411-39.
doi: 10.3390/molecules191015411.

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

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

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

Alicia Foucourt et al. Molecules. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Structures of previous molecules (see part 1 [9]), which inspired the current work.
Scheme 2
Scheme 2
Envisioned transformations of 1 for synthesis of novel compounds of series C.
Scheme 3
Scheme 3
Multistep synthesis of the key benzothiazole 1.
Scheme 4
Scheme 4
Synthesis of 7, 8 and 9 series via transformation of 4, 5 and 6 series.
Scheme 5
Scheme 5
Synthesis of 9N-methylated derivatives of 7a, 7c and 7e.
Scheme 6
Scheme 6
Synthesis of ethyl, isopropyl and benzyl carbimidates 12a–c and methyl carboxylate 13 from carbonitrile 7b.
Scheme 7
Scheme 7
Structure of the DYRK1A/1B reference compounds used in this study.
Scheme 8
Scheme 8
Structures and DYRK1A/1B IC50 values of the five lead compounds identified in this study (ClogP were calculated with Chemdraw V12.0).
See this image and copyright information in PMC

References

    1. Martin L., Latypova X., Wilson C.M., Magnaudeix A., Perrin M.-L., Terro F. Tau protein kinases: Involvement in Alzheimer’s disease. Ageing Res. Rev. 2013;12:289–309. doi: 10.1016/j.arr.2012.06.003. - DOI - PubMed
    1. Flajolet M., He G., Heiman M., Lin A., Nairn A.C., Greengard P. Regulation of Alzheimer’s disease amyloid-β formation by casein kinase I. Proc. Nat. Acad. Sci. USA. 2007;104:4159–4164. doi: 10.1073/pnas.0611236104. - DOI - PMC - PubMed
    1. Weinmann H., Metternich R. Drug discovery process for kinase Inhibitors. ChemBioChem. 2005;6:455–459. this paper is the editorial of a special issue “Kinases in Drug Discovery”ChemBioChem2005, 6, 453–574. - PubMed
    1. Loidreau Y., Marchand P., Dubouilh-Benard C., Nourrisson M.-R., Duflos M., Loaëc N., Meijer L., Besson T. Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases. Eur. J. Med. Chem. 2013;59:283–295. doi: 10.1016/j.ejmech.2012.11.030. - DOI - PubMed
    1. Loidreau Y., Marchand P., Dubouilh-Benard C., Nourrisson M.-R., Duflos M., Lozach O., Loaëc N., Meijer L., Besson T. Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors. Eur. J. Med. Chem. 2012;58:171–183. doi: 10.1016/j.ejmech.2012.10.006. - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources