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 (Author), Carole Dubouilh-Benard (Author), Marie-Renée Nourrisson (Author), Nadège Loaëc (Author), Laurent Meijer (Author), Thierry Besson (Author), Pascal Marchand (Author)
• Format: Book
• Published: MDPI AG, 2020-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 9<i>H</i>-pyrimido[5,4-<i>b</i>]- and [4,5-<i>b</i>]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC₅₀ values.

Item Description

10.3390/ph13050089
1424-8247