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Loidreau Y.,University of Rouen | Marchand P.,University of Nantes | Dubouilh-Benard C.,University of Rouen | Nourrisson M.-R.,University of Nantes | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2013

Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N′-(2-cyanaryl)-N,N- dimethylformimidamide intermediates obtained by reaction of 3-amino-6- methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2- carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.© 2012 Elsevier Masson SAS. All rights reserved. Source


Loidreau Y.,Normandie University | Deau E.,Normandie University | Marchand P.,University of Nantes | Nourrisson M.-R.,University of Nantes | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2015

This paper reports the design and synthesis of a novel series of 8-arylpyrido[3g2,2g2:4,5]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)-Ng2-(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[3g2,2g2:4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/, GSK3α/beta;, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3g2,2g2:4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1 δ and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3g2,2g2:4,5]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 CK1 δ/and CLK1 showed that functionalization at position 7 of pyrido[3g2,2g2:4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1 δ/epies; P-loop and thus a complete loss of inhibitory activity. © 2014 Elsevier Masson SAS. Source


Hedou D.,INSA Rouen | Dubouilh-Benard C.,INSA Rouen | Loaec N.,Protein Phosphorylation and Human Disease Group | Fruit C.,INSA Rouen | Besson T.,INSA Rouen
Molecules | Year: 2016

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. © 2016 by the authors; licensee MDPI. Source


Hedou D.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Godeau J.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Loaec N.,Protein Phosphorylation and Human Disease Group | Fruit C.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Besson T.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis
Molecules | Year: 2016

A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano-benzo[d] thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer's disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases. © 2016 by the authors; licensee MDPI. Source


Waiker D.K.,Rajiv Gandhi Technical University | Karthikeyan C.,Rajiv Gandhi Technical University | Poongavanam V.,University of Southern Denmark | Kongsted J.,University of Southern Denmark | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

A series of novel 4-anilinoquinazoline derivatives (3a-3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimer's disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3α/β kinase with IC50 values of 1.5 μM and 3 μM, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3β. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3α/β enzymes with potential therapeutic application in Alzheimer's disease. © 2014 Elsevier Ltd. All rights reserved. Source

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