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Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives.

ABSTRACT: We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1?/?, GSK3???? and DYRK1A). As a result, we have identified promising compounds targeting CK1?/? and DYRK1A and displaying micromolar and submicromolar IC50 values.

SUBMITTER: Loidreau Y 

PROVIDER: S-EPMC7281298 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Exploring Kinase Inhibition Properties of 9<i>H</i>-pyrimido[5,4-<i>b</i>]- and [4,5-<i>b</i>]indol-4-amine Derivatives.

Loidreau Yvonnick Y   Dubouilh-Benard Carole C   Nourrisson Marie-Renée MR   Loaëc Nadège N   Meijer Laurent L   Besson Thierry T   Marchand Pascal P  

Pharmaceuticals (Basel, Switzerland) 20200509 5

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC<sub>50</sub> values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiop  ...[more]

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