Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II
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 deriva...
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MDPI AG
2014-09-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/19/10/15411 |
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| author | Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Angélique Girard Thierry Taverne Anne-Sophie Casagrande Laurent Désiré Bertrand Leblond Thierry Besson |
| author_facet | Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Angélique Girard Thierry Taverne Anne-Sophie Casagrande Laurent Désiré Bertrand Leblond Thierry Besson |
| author_sort | Alicia Foucourt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T08:44:15Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-21T08:44:15Z |
| publishDate | 2014-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-793f87bb04ca4bb9ac2398e42af6e9d52022-12-21T19:09:53ZengMDPI AGMolecules1420-30492014-09-011910154111543910.3390/molecules191015411molecules191015411Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part IIAlicia Foucourt0Damien Hédou1Carole Dubouilh-Benard2Angélique Girard3Thierry Taverne4Anne-Sophie Casagrande5Laurent Désiré6Bertrand Leblond7Thierry Besson8Normandie 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, FranceNormandie 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, FranceNormandie 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, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceDiaxonhit, 65 boulevard Masséna, Paris F-75013, FranceNormandie 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, FranceThe 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.http://www.mdpi.com/1420-3049/19/10/15411thiazolo[5,4-f]quinazolineskinase inhibitorsDYRK1ADYRK1Bmicrowave-assisted chemistryDimroth rearrangementEHT 5372EHT 6840EHT 1610EHT 9851EHT 3356 |
| spellingShingle | Alicia Foucourt Damien Hédou Carole Dubouilh-Benard Angélique Girard Thierry Taverne Anne-Sophie Casagrande Laurent Désiré Bertrand Leblond Thierry Besson Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II Molecules thiazolo[5,4-f]quinazolines kinase inhibitors DYRK1A DYRK1B microwave-assisted chemistry Dimroth rearrangement EHT 5372 EHT 6840 EHT 1610 EHT 9851 EHT 3356 |
| title | Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II |
| title_full | Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II |
| title_fullStr | Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II |
| title_full_unstemmed | Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II |
| title_short | Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II |
| title_sort | design and synthesis of thiazolo 5 4 f quinazolines as dyrk1a inhibitors part ii |
| topic | thiazolo[5,4-f]quinazolines kinase inhibitors DYRK1A DYRK1B microwave-assisted chemistry Dimroth rearrangement EHT 5372 EHT 6840 EHT 1610 EHT 9851 EHT 3356 |
| url | http://www.mdpi.com/1420-3049/19/10/15411 |
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