Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors
A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N -ethoxycarbonyl- N ′-(hetero) arylguanidines at 130 ° C in water. The cyclization is fully regioselective....
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| Veröffentlicht in: | Molecular diversity 2012-11, Vol.16 (4), p.659-667 |
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| container_title | Molecular diversity |
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| creator | Debray, Julien Bonte, Simon Lozach, Olivier Meijer, Laurent Demeunynck, Martine |
| description | A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of
N
-ethoxycarbonyl-
N
′-(hetero) arylguanidines at 130 °
C
in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-
f
]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design. |
| doi_str_mv | 10.1007/s11030-012-9397-7 |
| format | Article |
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N
-ethoxycarbonyl-
N
′-(hetero) arylguanidines at 130 °
C
in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-
f
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N
-ethoxycarbonyl-
N
′-(hetero) arylguanidines at 130 °
C
in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-
f
]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Catalysis</subject><subject>Cyclization</subject><subject>Drug Design</subject><subject>Dyrk Kinases</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Escherichia coli</subject><subject>Full-Length Paper</subject><subject>Guanidines - chemistry</subject><subject>Hot Temperature</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Nitrogen</subject><subject>Organic Chemistry</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Polymer Sciences</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Quinazolinones - chemical synthesis</subject><subject>Rats</subject><subject>Recombinant Proteins - metabolism</subject><subject>Swine</subject><subject>Transition Temperature</subject><issn>1381-1991</issn><issn>1573-501X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kdFq1jAYhosobk4vwBMJeDJh0XxJ26Q7G79ujg0EUVBEQtom-zPapEtSpF6U12jqP2UKHiXke94nIW9RPAXyEgjhryIAYQQToLhhDcf8XrEPFWe4IvDpft4zARiaBvaKRzFeE5JTwB4We5TmQ8LL_eLHRiU1LDFhE7RGcXFpq6ONyBt0M1unvvvBOlxi73REJvgRHW510sG_UGEZ8NWsnO1tHh4jNU2D7VSy3qHkURb97ZuWsOr8l_KIYfP1jr75pT9CCjn9DRk12mFZE68_v7-AE2Td1rY2-RAfFw-MGqJ-crseFB9P33zYvMWX787ONyeXuCuZSLhvBa2qlja8F6wltGWUElN1ZUXKvi4Z0XXdlVAJYWgGe82ggrw1XHVKCcEOisOddwr-ZtYxydHGTg-DctrPUUL2sZoLsqLP_0Gv_Rxcfp0EaDgIqFmTKdhRXfAxBm3kFOyYv1ACkWuZclemzGXKtUzJc-bZrXluR93_SfxuLwN0B8Q8clc63Ln6v9afy3arCQ</recordid><startdate>20121101</startdate><enddate>20121101</enddate><creator>Debray, Julien</creator><creator>Bonte, Simon</creator><creator>Lozach, Olivier</creator><creator>Meijer, Laurent</creator><creator>Demeunynck, Martine</creator><general>Springer Netherlands</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20121101</creationdate><title>Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors</title><author>Debray, Julien ; 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The key step of the two-step process involves the environmental friendly thermolysis of
N
-ethoxycarbonyl-
N
′-(hetero) arylguanidines at 130 °
C
in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-
f
]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>22991074</pmid><doi>10.1007/s11030-012-9397-7</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1381-1991 |
| ispartof | Molecular diversity, 2012-11, Vol.16 (4), p.659-667 |
| issn | 1381-1991 1573-501X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1220367808 |
| source | MEDLINE; SpringerLink Journals |
| subjects | Animals Biochemistry Catalysis Cyclization Drug Design Dyrk Kinases Enzyme Inhibitors - chemical synthesis Escherichia coli Full-Length Paper Guanidines - chemistry Hot Temperature Humans Inhibitor drugs Kinases Life Sciences Mice Molecular Structure Nitrogen Organic Chemistry Pharmaceutical sciences Pharmacy Polymer Sciences Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism Quinazolinones - chemical synthesis Rats Recombinant Proteins - metabolism Swine Transition Temperature |
| title | Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors |
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