title: Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors.
abstract: This paper reports the design and synthesis of a novel series of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N'-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity.
authors.affiliation: Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.
authors.forename: Yvonnick
authors.initials: Y
authors.lastname: Loidreau
authors.affiliation: Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deau
authors.affiliation: Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Marchand
authors.affiliation: Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.
authors.forename: Marie-Renée
authors.initials: MR
authors.lastname: Nourrisson
authors.affiliation: Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.affiliation: Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Coadou
authors.affiliation: Protein Phosphorylation & Human Disease Group, Station Biologique, 29680 Roscoff, France; Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France. Electronic address: thierry.besson@univ-rouen.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Besson
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017346:Protein Serine-Threonine Kinases
keywords: Alzheimer disease; Kinase inhibitors; Microwave-assisted chemistry; Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines