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.
abstract: 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.
authors.affiliation: Département de Pharmacochimie Moléculaire, UMR 5063 & ICMG FR-2607, CNRS/Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Debray
authors.forename: Simon
authors.initials: S
authors.lastname: Bonte
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Martine
authors.initials: M
authors.lastname: Demeunynck
mesh_terms: D000818:Animals; D002384:Catalysis; D003500:Cyclization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004926:Escherichia coli; D006146:Guanidines / Q000737:chemistry*; D006358:Hot Temperature; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine; D044366:Transition Temperature; D000097603:Dyrk Kinases
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D052999:Quinazolinones; D011994:Recombinant Proteins; D000097603:Dyrk Kinases; C066780:Clk dual-specificity kinases