Synthesis and molecular modelling studies of 8-arylpyrido[30,20:4,5] thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors

Article abstract of DOI:10.1016/j.ejmech.2014.12.038

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/β, 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.