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

• Main Authors: Yvonnick Loidreau, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Nadège Loaëc, Laurent Meijer, Thierry Besson, Pascal Marchand
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Pharmaceuticals
• Subjects: microwave-assisted chemistry; protein kinases; CK1; DYRK1A; CDK5; GSK-3
• Online Access: https://www.mdpi.com/1424-8247/13/5/89

<b> </b>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/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC₅₀ values.