Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation.
A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer's disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France. d.hedou@laposte.net.
Damien
D
Hédou
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France. carole.dubouilh@univ-rouen.fr.
Carole
C
Dubouilh-Benard
Protein Phosphorylation &amp; Human Disease group, Station Biologique, 29680 Roscoff, France. Nadege.Loaec@univ-brest.fr.|Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France. Nadege.Loaec@univ-brest.fr.
Nadège
N
Loaëc
Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France. meijer@manros-therapeutics.com.
Laurent
L
Meijer
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France. corinne.fruit@univ-rouen.fr.
Corinne
C
Fruit
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France. thierry.besson@univ-rouen.fr.
Thierry
T
Besson
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D001463:Barbiturates / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D001463:Barbiturates; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D003300:Copper; C061339:4-hydroxyquinazoline; C022044:5-nitrobarbituric acid
CDK5; CK1; CLK1; DYRK1A; GSK-3; Hügershoff reaction; microwave-assisted synthesis; protein kinases; thiazolo[5,4-f]quinazolin-9(8H)-ones