Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5thieno[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.
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Submitted on : Tuesday, March 24, 2015 - 8:50:03 PM
Last modification on : Thursday, March 21, 2019 - 1:01:21 PM

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Yvonnick Loidreau, Emmanuel Deau, Pascal Marchand, Marie-Renée Nourrisson, Cédric Logé, et al.. Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors. European Journal of Medicinal Chemistry, Elsevier, 2015, 92, pp.124-134. ⟨10.1016/j.ejmech.2014.12.038⟩. ⟨hal-01135195⟩

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